背景技术Background technique
电化学葡萄糖测试条，诸如用于全血测试试剂盒(可购自LifeScan公司)中的那些，设计用于测量糖尿病患者的生理流体样品中的葡萄糖浓度。葡萄糖的测量可基于葡萄糖氧化酶(GO)对葡萄糖的选择性氧化来进行。葡萄糖测试条中可发生的反应由下面的公式1和公式2来概括。Electrochemical glucose test strips, such as those used in Those in the Whole Blood Test Kit (commercially available from LifeScan Corporation) are designed to measure glucose concentrations in physiological fluid samples of diabetic patients. The measurement of glucose can be based on the selective oxidation of glucose by glucose oxidase (GO). The reactions that can occur in a glucose test strip are summarized by Equation 1 and Equation 2 below.
公式1 葡萄糖+GO(氧化)→葡糖酸+GO(还原)Formula 1 Glucose + GO(oxidation) → Gluconic acid + GO(reduction)
公式2 GO(还原)+2Fe(CN)63-→GO(氧化)+2Fe(CN)64-Formula 2 GO(reduction) +2Fe(CN)63- → GO(oxidation) +2Fe(CN)64-
如公式1中所示，葡萄糖被葡萄糖氧化酶的氧化形式(GO(氧化))氧化成葡糖酸。应当指出的是，GO(氧化)还可被称为“氧化的酶”。在公式1的反应期间，氧化的酶GO(氧化)被转化为其还原状态，其被表示为GO(还原)(即，“还原的酶”)。接着，如公式2中所示，还原的酶GO(还原)通过与Fe(CN)63-(被称为氧化介体或铁氰化物)的反应而被再氧化回GO(氧化)。在GO(还原)重新生成回其氧化态GO(氧化)期间，Fe(CN)63-被还原成Fe(CN)64-(被称为还原介体或亚铁氰化物)。As shown in Equation 1, glucose is oxidized to gluconic acid by the oxidized form of glucose oxidase (GO(oxid) ). It should be noted that GO(Oxidation) can also be referred to as "oxidative enzyme". During the reaction of Formula 1, the oxidized enzyme GO(oxidize) is converted to its reduced state, which is denoted as GO(reduce) (ie, "reduced enzyme"). Next, as shown in Equation 2, the reduced enzyme GO(reduce) is reoxidized back to GO(oxidize) by reaction with Fe(CN)63− (known as oxidation mediator or ferricyanide). During the regeneration of GO(reduction) back to its oxidation state GO(oxidation) , Fe(CN)63- is reduced to Fe(CN)64- (known as reduced mediator or ferrocyanide).
当利用施加于两个电极之间的测试信号进行上述反应时，可通过在电极表面处经还原介体的电化学再氧化生成测试电流。因此，由于在理想环境下，上述化学反应期间生成的亚铁氰化物的量与定位在电极之间的样品中葡萄糖的量成正比，所以生成的测试电流将与样品的葡萄糖含量成比例。诸如铁氰化物的介体是接受来自酶(诸如葡萄糖氧化酶)的电子并随后将电子供给电极的化合物。随着样品中的葡萄糖浓度增加，所形成的还原介体的量也增加；因此，源自还原介体再氧化的测试电流与葡萄糖浓度之间存在直接关系。具体地，电子在整个电界面上的传输致使测试电流流动(每摩尔被氧化的葡萄糖对应2摩尔电子)。因此，由于葡萄糖的引入而产生的测试电流可被称为葡萄糖信号。When the above reaction is performed with a test signal applied between two electrodes, a test current can be generated by electrochemical reoxidation of the reduced mediator at the electrode surface. Therefore, since the amount of ferrocyanide generated during the chemical reaction described above is ideally proportional to the amount of glucose in the sample positioned between the electrodes, the generated test current will be proportional to the glucose content of the sample. A mediator such as ferricyanide is a compound that accepts electrons from an enzyme such as glucose oxidase and then donates the electrons to an electrode. As the concentration of glucose in the sample increases, so does the amount of reduced mediator formed; therefore, there is a direct relationship between the test current resulting from reoxidation of the reduced mediator and the glucose concentration. Specifically, transport of electrons across the electrical interface causes a test current to flow (2 moles of electrons per mole of oxidized glucose). Therefore, the test current due to the introduction of glucose can be referred to as a glucose signal.
当某些血液成分存在时，会对测量产生不良影响并导致检测信号不准确，从而对电化学生物传感器产生负面影响。例如，测量不准确可导致葡萄糖读数不准确，从而使得患者无法察觉潜在地危险的血糖含量。作为一个示例，血液的血细胞比容含量(即红细胞在血液中所占的量的百分比)会对所得分析物浓度的测量造成错误影响。When certain blood components are present, they can adversely affect the measurement and lead to inaccurate detection signals, thus negatively affecting electrochemical biosensors. For example, inaccurate measurements can lead to inaccurate glucose readings, thereby leaving the patient unaware of potentially dangerous blood sugar levels. As an example, the hematocrit content of blood (ie, the percentage of red blood cells in the blood) can falsely affect the resulting analyte concentration measurement.
血液中红细胞容积的变化会使一次性电化学测试条所测量的葡萄糖读数出现差异。通常，高血细胞比容下会出现负偏差(即计算出的分析物浓度偏低)，低血细胞比容下会出现正偏差(即与参考分析物浓度相比，计算出的分析物浓度偏高)。在高血细胞比容下，例如，血红细胞可能会阻碍酶与电化学介体的反应，降低化学溶解速率，因为用于使化学反应物成溶剂化物的血浆量较低并且介体的扩散速度慢。这些因素会造成比预期的葡萄糖读数低，因为电化学过程期间产生的信号较小。相反，在低血细胞比容下，可影响电化学反应的红细胞数量比预期要少，因而测量的信号也更大。此外，生理流体样品电阻也与血细胞比容相关，这会影响电压和/或电流测量。Changes in the volume of red blood cells in the blood can cause differences in the glucose readings measured by the disposable electrochemical test strips. Typically, negative bias (i.e., low calculated analyte concentration) occurs at high hematocrit and positive bias (i.e., high calculated analyte concentration compared to the reference analyte concentration) occurs at low hematocrit ). At high hematocrit, for example, red blood cells may hinder the reaction of enzymes with electrochemical mediators, reducing the rate of chemical dissolution because of the low volume of plasma used to solvate chemical reactants and slow diffusion of mediators . These factors can cause lower than expected glucose readings due to the smaller signal generated during the electrochemical process. Conversely, at low hematocrit, there are fewer red blood cells than expected to affect the electrochemical reaction, and the measured signal is greater. In addition, physiological fluid sample resistance is also related to hematocrit, which affects voltage and/or current measurements.
目前已采用了若干策略来降低或避免基于血细胞比容的变型对血糖造成的影响。例如，测试条已被设计成结合可将样品中的红细胞去除的多个筛目，或者已含有多种化合物或制剂，用以提高红细胞的粘度并减弱低血细胞比容对浓度确定的影响。为了校正血细胞比容，其它测试条已包括细胞溶解剂和被配置成确定血红蛋白浓度的系统。另外，生物传感器已被配置成通过下述方式来测量血细胞比容：测量经由交变电流信号的流体样品的电响应或利用光照射生理流体样品之后的光学变型的变化，或者基于样品室填充时间的函数来测量血细胞比容。这些传感器具有某些缺点。涉及血细胞比容检测的策略的通用技术为使用所测量的血细胞比容值来校正或改变所测量的分析物浓度，所述技术通常示于和描述于下述相应的美国专利申请公布2010/0283488、2010/0206749、2009/0236237、2010/0276303、2010/0206749、2009/0223834、2008/0083618、2004/0079652、2010/0283488、2010/0206749、2009/0194432或美国专利7,972,861和7,258,769中，所有这些专利申请公布和专利据此均以引用方式并入本申请。Several strategies have been employed to reduce or avoid the effect of hematocrit-based variants on blood glucose. For example, test strips have been designed to incorporate multiple meshes that remove red blood cells from the sample, or have contained compounds or agents that increase the viscosity of red blood cells and attenuate the effect of low hematocrit on concentration determination. To correct for hematocrit, other test strips have included a cell lysing agent and a system configured to determine hemoglobin concentration. In addition, biosensors have been configured to measure hematocrit by measuring the electrical response of a fluid sample via an alternating current signal or the change in optical distortion following illumination of a physiological fluid sample with light, or based on sample chamber fill time function to measure hematocrit. These sensors have certain disadvantages. A general technique for strategies involving hematocrit detection is to use the measured hematocrit value to correct or alter the measured analyte concentration, which is generally shown and described in the corresponding U.S. Patent Application Publication 2010/0283488 below 、2010/0206749、2009/0236237、2010/0276303、2010/0206749、2009/0223834、2008/0083618、2004/0079652、2010/0283488、2010/0206749、2009/0194432或美国专利7,972,861和7,258,769中，所有这些Both patent application publications and patents are hereby incorporated by reference into this application.
发明内容Contents of the invention
申请人已设计出包括测试条和分析物测量仪的分析物测量系统。该试纸条包括衬底、连接至相应电极连接器的多个电极，其中试剂靠近多个电极设置。该测量仪包括外壳、被配置成连接至测试条的相应电极连接器的测试条端口连接器、和微处理器，该微处理器与该测试条端口连接器电连通以施加电信号或测量来自多个电极的电信号。微处理器被配置成：(a)将第一信号施加至多个电极，使得确定流体样品的物理特性；(b)将第二信号施加至多个电极的第一电极和第二电极；(c)靠近指定取样时间点、从第一电极和第二电极中的每个电极测量来自电极的信号输出；(d)靠近预定取样时间点、从第一电极和第二电极中的每个电极测量来自电极的另一个信号输出；(e)计算在指定取样时间点处测量的第一电极的信号输出和在预定取样时间点处测量的第一电极的信号输出之间的第一差动；(f)计算在指定取样时间点处测量的第二电极的信号输出和在预定取样时间点处测量的第二电极的信号输出之间的第二差动；(g)评估第一差动和第二差动中的任一个是否小于预定阈值；并且(h)如果第一差动和第二差动中的一个小于偏置阈值，则通告错误。Applicants have designed an analyte measurement system that includes a test strip and an analyte meter. The test strip includes a substrate, a plurality of electrodes connected to corresponding electrode connectors, wherein a reagent is disposed proximate to the plurality of electrodes. The meter includes a housing, a test strip port connector configured to connect to a corresponding electrode connector of a test strip, and a microprocessor in electrical communication with the test strip port connector to apply an electrical signal or measure an electrical signal from Electrical signals from multiple electrodes. The microprocessor is configured to: (a) apply the first signal to the plurality of electrodes such that a physical characteristic of the fluid sample is determined; (b) apply the second signal to the first electrode and the second electrode of the plurality of electrodes; (c) Close to the specified sampling time point, from each electrode in the first electrode and the second electrode, measure the signal output from the electrode; (d) measure the signal output from each electrode near the predetermined sampling time point, from the first electrode and the second electrode Another signal output of the electrode; (e) calculating a first difference between the signal output of the first electrode measured at the specified sampling time point and the signal output of the first electrode measured at the predetermined sampling time point; (f ) calculating a second difference between the signal output of the second electrode measured at a specified sampling time point and the signal output of the second electrode measured at a predetermined sampling time point; (g) evaluating the first difference and the second difference whether either of the differentials is less than a predetermined threshold; and (h) if one of the first differential and the second differential is less than the offset threshold, an error is declared.
因此，在前面所述实施方案的任一个中，以下特征也可与前文所公开的实施方案以多种组合使用。例如，多个电极可以包括四个电极，其中第一电极和第二电极来测量分析物浓度，并且第三电极和第四电极来测量物理特性；第一电极、第二电极、第三电极和第四电极设置在提供于衬底上的相同腔室中；第一电极和第二电极以及第三电极和第四电极设置在提供于衬底上的相应两个不同腔室中；所有电极均设置在由衬底限定的相同平面上；将试剂靠近至少两个其它电极设置，并且不将试剂设置在至少两个电极上；由在测试序列启动约10秒内的第二信号来确定最终分析物浓度，并且偏置阈值可包括约10纳安至约1000纳安的任何值；取样时间点选自包括矩阵的查找表，其中所估计的分析物的不同定性类别在矩阵的最左列中列出，并且所测量的或估计的物理特性的不同定性类别在矩阵的最顶行中列出，并且取样时间提供在矩阵的剩余单元格中。Thus, in any of the previously described embodiments, the following features may also be used in various combinations with the previously disclosed embodiments. For example, the plurality of electrodes may include four electrodes, wherein a first electrode and a second electrode are used to measure an analyte concentration, and a third electrode and a fourth electrode are used to measure a physical property; the first electrode, the second electrode, the third electrode and the The fourth electrode is provided in the same chamber provided on the substrate; the first electrode and the second electrode and the third electrode and the fourth electrode are provided in respective two different chambers provided on the substrate; all electrodes are Disposed on the same plane defined by the substrate; disposes reagents close to at least two other electrodes and does not dispose reagents on at least two electrodes; final analysis is determined by a second signal within about 10 seconds of initiation of the test sequence concentration of the analyte, and the bias threshold can include any value from about 10 nanoamperes to about 1000 nanoamperes; the sampling time point is selected from a lookup table comprising a matrix, wherein the different qualitative classes of the estimated analytes are in the leftmost column of the matrix are listed, and the different qualitative categories of the measured or estimated physical properties are listed in the topmost row of the matrix, and the sampling times are provided in the remaining cells of the matrix.
在本公开的附加方面，存在计算机可读介质，每个介质包括可执行指令，该可执行指令在由计算机执行时进行上述方法中的任何一个方法的步骤。In an additional aspect of the present disclosure, there are computer-readable media, each comprising executable instructions that, when executed by a computer, perform the steps of any one of the methods described above.
在本公开的附加方面，存在诸如测试仪或分析物测试装置的装置，每个装置或测量仪包括被配置成执行上述方法中的任一方法的步骤的电子电路或处理器。In an additional aspect of the disclosure, there are devices such as test meters or analyte testing devices, each device or meter comprising electronic circuitry or a processor configured to perform the steps of any of the methods described above.
对于本领域的技术人员而言，当结合将被首先简要描述的附图来参考以下对本发明的示例性实施方案的更详细说明时，这些和其它实施方案、特征和优点将变得显而易见。These and other embodiments, features and advantages will become apparent to those skilled in the art when reference is made to the following more detailed description of exemplary embodiments of the invention in conjunction with the accompanying drawings, which will first be briefly described.
附图说明Description of drawings
并入本文中并且构成本说明书一部分的附图示出本发明当前优选的实施方案，并且与上面所给出的概述和下面所给出的详述一起用于解释本发明的特征(其中类似的数字表示类似的元件)，其中：The accompanying drawings, which are incorporated herein and constitute a part of this specification, illustrate presently preferred embodiments of the invention and, together with the General Description given above and the Detailed Description given below, serve to explain the features of the invention (where similar Numbers indicate similar components), where:
图1A示出了包括测量仪和生物传感器的分析物测量系统。Figure 1A shows an analyte measurement system including a meter and a biosensor.
图1B示出了包括测量仪和生物传感器的另一个分析物测量系统。Figure IB shows another analyte measurement system including a meter and a biosensor.
图2A以简化示意图形式示出了测量仪200的部件。Figure 2A shows the components of gauge 200 in simplified schematic form.
图2B以简化示意图形式示出了测量仪200的变型的优选具体实施。FIG. 2B shows a preferred implementation of a variant of meter 200 in simplified schematic form.
图2C为图1A和图1B的手持式测试仪的多个块的简化框图。2C is a simplified block diagram of various blocks of the handheld tester of FIGS. 1A and 1B .
图2D为如可在根据本公开的实施方案中采用的物理特性测量块的简化框图。Figure 2D is a simplified block diagram of a physical property measurement block as may be employed in an embodiment according to the present disclosure.
图3A示出了图1的系统的测试条100，其中存在位于测量电极的上游的两个物理特性感测电极。FIG. 3A shows the test strip 100 of the system of FIG. 1 in which there are two physical property sensing electrodes upstream of the measurement electrodes.
图3B示出了图3A的测试条的变型，其中提供了屏蔽或接地电极用于靠近测试腔室的入口。Figure 3B shows a variation of the test strip of Figure 3A in which a shield or ground electrode is provided for proximity to the entrance of the test chamber.
图3C示出了图3A和图3B的测试条100的变型，其中测试条的某些部件已被一起整合成单个单元。FIG. 3C shows a variation of the test strip 100 of FIGS. 3A and 3B in which certain components of the test strip have been integrated together into a single unit.
图4A示出了时间相对于施加至图3A、图3B或图3C的生物传感器的电势的曲线图。Figure 4A shows a graph of time versus potential applied to the biosensor of Figure 3A, Figure 3B, or Figure 3C.
图4B示出了时间相对于来自图3A、图3B或图3C的生物传感器的输出电流的曲线图。Figure 4B shows a graph of time versus output current from the biosensor of Figure 3A, Figure 3B, or Figure 3C.
图5示出了用以确定分析物测量的波形输出信号瞬态中的错误的逻辑流程图。Figure 5 shows a logic flow diagram for determining errors in a waveform output signal transient for an analyte measurement.
具体实施方式detailed description
应参考附图来阅读下面的具体实施方式，其中不同附图中类似要素相同地编号。未必按比例绘制的附图描绘所选择的实施方案，并不旨在限制本发明的范围。具体实施方式以举例的方式而不是限制性方式示出本发明的原理。该具体实施方式将清楚地使本领域的技术人员能够制备和使用本发明，并且描述了本发明的若干实施方案、改型、变型、替代方案和用途，包括目前据信是实施本发明的最佳模式。The following Detailed Description should be read with reference to the accompanying drawings, in which like elements are numbered the same in different drawings. The drawings, which are not necessarily to scale, depict selected embodiments and are not intended to limit the scope of the invention. The detailed description illustrates the principles of the invention by way of example and not limitation. This detailed description will clearly enable those skilled in the art to make and use the invention, and describes several embodiments, adaptations, variations, alternatives, and uses of the invention, including what is presently believed to be the best way to practice the invention. best mode.
如本文所用，针对任何数值或范围的术语“约”或“大约”指示允许零件或多个部件的集合执行如本文所述的其指定用途的合适的尺寸公差。更具体地，“约”或“大约”可指列举值的值±10％的范围，例如“约90％”可指81％至99％的值范围。另外，如本文所用，术语“患者”、“宿主”、“用户”和“受检者”是指任何人或动物受检者，并不旨在将系统或方法局限于人使用，但本主题发明在人类患者中的使用代表优选的实施方案。如本文所用，“振荡信号”包括分别改变极性、或交变电流方向、或为多向的电压信号或电流信号。还如本文所用，短语“电信号”或“信号”旨在包括直流信号、交变信号或电磁谱内的任何信号。术语“处理器”、“微处理器”、或“微控制器”旨在具有相同的含义并且旨在可互换使用。如本文所用，术语“通告”及其根源术语的变型指示可经由文本、音频、视频或者所有通信模式或通信介质的组合向用户提供通告。As used herein, the term "about" or "approximately" for any numerical value or range indicates a suitable dimensional tolerance that allows the part or collection of components to perform for its intended purpose as described herein. More specifically, "about" or "approximately" may refer to a range of ±10% of the value of a recited value, eg "about 90%" may refer to a range of values of 81% to 99%. Additionally, the terms "patient," "host," "user," and "subject," as used herein, refer to any human or animal subject and are not intended to limit the system or method to human use, but the subject matter Use of the invention in human patients represents a preferred embodiment. As used herein, "oscillating signal" includes a voltage signal or a current signal that changes polarity, or alternates current direction, or is multidirectional, respectively. Also as used herein, the phrase "electrical signal" or "signal" is intended to include direct current signals, alternating signals, or any signal within the electromagnetic spectrum. The terms "processor", "microprocessor", or "microcontroller" are intended to have the same meaning and are intended to be used interchangeably. As used herein, the term "announcement" and variations of its root term indicate that an announcement may be provided to a user via text, audio, video, or a combination of all modes or media of communication.
图1A示出了利用通过本文所示和所述的方法和技术生产的生物传感器来测试个体的血液中分析物(例如，葡萄糖)水平的测试仪200。测试仪200可包括用户界面输入(206、210、214)，其可采取按钮的形式，用于输入数据、菜单导航和执行命令。数据可包括表示分析物浓度的值和/或与个体的日常生活方式相关的信息。与日常生活方式相关的信息可包括个体的食物摄取、药物使用、健康检查的发生率、总体健康状态和运动水平。测试仪200还可包括显示器204，其可用于报告所测量的葡萄糖水平，且便于进入生活方式相关的信息。FIG. 1A shows a tester 200 for testing an individual's blood level of an analyte (eg, glucose) using a biosensor produced by the methods and techniques shown and described herein. Tester 200 may include user interface inputs (206, 210, 214), which may take the form of buttons, for entering data, navigating menus, and executing commands. Data may include values indicative of analyte concentrations and/or information related to the individual's daily lifestyle. Information related to daily life style may include an individual's food intake, medication use, incidence of health checkups, general health status, and exercise level. The test meter 200 may also include a display 204, which may be used to report measured glucose levels and facilitate access to lifestyle related information.
测试仪200可包括第一用户界面输入206、第二用户界面输入210和第三用户界面输入214。用户界面输入206、210和214便于进入和分析存储在测试装置中的数据，从而使用户能够通过显示器204上显示的用户界面进行导航。用户界面输入206、210和214包括第一标记208、第二标记212和第三标记216，其有助于将用户界面输入与显示器204上的字符相关联。Tester 200 may include first user interface input 206 , second user interface input 210 , and third user interface input 214 . User interface inputs 206 , 210 , and 214 facilitate accessing and analyzing data stored in the test device, thereby enabling a user to navigate through the user interface displayed on display 204 . User interface inputs 206 , 210 , and 214 include first indicia 208 , second indicia 212 , and third indicia 216 that facilitate associating the user interface inputs with characters on display 204 .
可通过将生物传感器100(或其变型)插入到条端口连接器220中、通过按压并短暂地保持第一用户界面输入206、或者通过检测整个数据端口218上的数据流量来开启测试仪200。可通过移除生物传感器100(或其变型)、按压并短暂地保持第一用户界面输入206、导航到主菜单屏幕并从主菜单屏幕选择测量仪关闭选项、或者通过在预定时间内不按压任何按钮来关闭测试仪200。显示器104可任选地包括背光。The tester 200 can be turned on by inserting the biosensor 100 (or a variant thereof) into the strip port connector 220 , by pressing and briefly holding the first user interface input 206 , or by detecting data traffic on the entire data port 218 . This can be done by removing biosensor 100 (or a variation thereof), pressing and briefly holding first user interface input 206, navigating to the main menu screen and selecting the meter off option from the main menu screen, or by not pressing any button for a predetermined period of time. button to turn off the tester 200. Display 104 may optionally include a backlight.
在一个实施方案中，测试仪200可被配置成在例如从第一测试条批转换到第二测试条批时不从任何外部源接收校准输入。因此，在一个示例性实施方案中，测量仪被配置成不从外部源接收校准输入，所述外部源诸如用户界面(诸如输入206、210、214)、所插入的测试条、单独的代码键或代码条、数据端口218。当所有生物传感器批具有基本一致的校准特性时，此类校准输入是不必要的。校准输入可为赋予特定生物传感器批的一组值。例如，校准输入可包括特定生物传感器批的批“斜率”值和批“截距”值。校准输入(诸如批斜率和截距值)可预设在测量仪中，如下文将描述。In one embodiment, the test meter 200 may be configured not to receive calibration input from any external source when switching, for example, from a first test strip lot to a second test strip lot. Thus, in an exemplary embodiment, the meter is configured not to receive calibration input from external sources, such as user interfaces (such as inputs 206, 210, 214), inserted test strips, separate code keys or code strip, data port 218. Such calibration input is unnecessary when all biosensor batches have substantially consistent calibration characteristics. A calibration input can be a set of values assigned to a particular biosensor lot. For example, calibration inputs may include batch "slope" values and batch "intercept" values for a particular biosensor batch. Calibration inputs, such as batch slope and intercept values, can be preset in the meter, as will be described below.
参考图2A，示出了测试仪200的示例性内部布局。测试仪200可包括处理器300，其在本文所述和所示的一些实施方案中为32位的RISC微控制器。在本文所述和所示的优选实施方案中，处理器300优选地选自由Texas Instruments(Dallas Texas)制造的MSP430系列超低功率微控制器。处理器可经由I/O端口314双向连接至存储器302，存储器302在本文所述和所示的一些实施方案中为EEPROM。另外经由I/O端口214连接至处理器300的是数据端口218、用户界面输入206、210和214以及显示驱动器320。数据端口218可连接至处理器300，由此使数据能够在存储器302和外部装置(诸如个人计算机)之间传输。用户界面输入206、210和214直接连接至处理器300。处理器300经由显示驱动器320控制显示器204。在测试仪200的生产期间，存储器302可预加载有校准信息，诸如批斜率和批截距值。在经由条端口连接器220从测试条接收到合适的信号(诸如电流)时，可由处理器300访问和使用预加载的校准信息，以便利用信号和校准信息计算出对应的分析物水平(诸如血糖浓度)，而不需从任何外部源接收校准输入。Referring to FIG. 2A , an exemplary internal layout of tester 200 is shown. Tester 200 may include processor 300, which in some embodiments described and illustrated herein is a 32-bit RISC microcontroller. In the preferred embodiment described and illustrated herein, the processor 300 is preferably selected from the MSP430 series of ultra-low power microcontrollers manufactured by Texas Instruments (Dallas Texas). The processor can be bi-directionally connected via I/O port 314 to memory 302, which in some embodiments described and illustrated herein is an EEPROM. Also connected to processor 300 via I/O port 214 are data port 218 , user interface inputs 206 , 210 , and 214 , and display driver 320 . A data port 218 is connectable to the processor 300, thereby enabling data to be transferred between the memory 302 and an external device such as a personal computer. User interface inputs 206 , 210 and 214 are directly connected to processor 300 . The processor 300 controls the display 204 via the display driver 320 . During production of tester 200, memory 302 may be preloaded with calibration information, such as batch slope and batch intercept values. Upon receipt of an appropriate signal (such as a current) from a test strip via strip port connector 220, the preloaded calibration information can be accessed and used by processor 300 to calculate a corresponding analyte level (such as a blood glucose level) using the signal and calibration information. concentration) without receiving calibration input from any external source.
在本文所述和所示的实施方案中，测试仪200可包括专用集成电路(ASIC)304，以便提供在测量血液中葡萄糖水平中使用的电子电路，该血液已施加至插入到条端口连接器220中的测试条100(或其变型)。模拟电压可通过模拟接口306传送到ASIC304或从ASIC 304传送出。来自模拟接口306的模拟信号可通过A/D转换器316转换为数字信号。处理器300还包括芯308、ROM 310(含有计算机代码)、RAM 312以及时钟318。在一个实施方案中，处理器300被配置成(或编程为)：诸如例如在分析物测量后的一个时间段使所有用户界面输入无效，除了在显示单元作出分析物值的显示时即进行的单个输入之外。在另选的实施方案中，处理器300配置成(或编程为)：忽略来自所有用户界面输入的任何输入，除了在显示单元作出分析物值的显示时即进行的单个输入之外。测量仪200的详细说明和阐释示于和描述于国际专利申请公布WO2006070200中，该专利申请据此以引用方式并入本申请，如同在本文完全阐述一样。In the embodiments described and illustrated herein, the test meter 200 may include an application-specific integrated circuit (ASIC) 304 to provide the electronic circuitry used in measuring glucose levels in blood that has been applied to a port connector inserted into the strip. Test strip 100 (or variations thereof) at 220 . Analog voltages may be communicated to or from ASIC 304 via analog interface 306 . Analog signals from analog interface 306 may be converted to digital signals by A/D converter 316 . Processor 300 also includes core 308 , ROM 310 (containing computer code), RAM 312 , and clock 318 . In one embodiment, the processor 300 is configured (or programmed) to invalidate all user interface inputs, such as, for example, for a period of time after an analyte measurement, except when a display of an analyte value is made by the display unit. beyond a single input. In an alternative embodiment, the processor 300 is configured (or programmed) to ignore any input from all user interface inputs except for a single input made at the time the display of the analyte value is made by the display unit. A detailed description and illustration of the gauge 200 is shown and described in International Patent Application Publication WO2006070200, which is hereby incorporated by reference into this application as if fully set forth herein.
参见图1B，提供了手持式测试仪200的另一个实施方案。该型式的测量仪200包括显示器102、多个用户界面按钮104、条端口连接器106、USB接口108以及外壳。参见图2A-图2D，图1A和图1B的手持式测试仪200还包括微控制器块112、物理特性测量块114、显示器控制块116、存储器块118和其它电子部件(未示出)，用于向生物传感器施加测试电压，并且还用于测量电化学响应(例如多个测试电流值)以及基于该电化学响应确定分析物。为了简化当前的描述，附图没有示出所有此类电子电路。Referring to FIG. 1B , another embodiment of a handheld tester 200 is provided. This version of meter 200 includes a display 102, a plurality of user interface buttons 104, a bar port connector 106, a USB interface 108, and a housing. Referring to FIGS. 2A-2D , the handheld tester 200 of FIGS. 1A and 1B also includes a microcontroller block 112, a physical characteristic measurement block 114, a display control block 116, a memory block 118 and other electronic components (not shown), Used to apply a test voltage to the biosensor, and also used to measure an electrochemical response (eg, a plurality of test current values) and determine an analyte based on the electrochemical response. To simplify the present description, the drawings do not show all such electronic circuits.
显示器102可以为例如被配置成显示屏幕图像的液晶显示器或双稳显示器。屏幕图像的示例可包括葡萄糖浓度、日期和时间、错误消息和用于指示最终用户如何执行测试的用户界面。Display 102 may be, for example, a liquid crystal display or a bi-stable display configured to display screen images. Examples of screen images may include glucose concentration, date and time, error messages, and a user interface for instructing the end user how to perform the test.
条端口连接器106被配置成与诸如基于电化学的生物传感器的生物传感器100可操作地进行交互，该基于电化学的生物传感器被配置用于确定全血样品中的葡萄糖。因此，生物传感器被配置用于可操作地插入到条端口连接器106中，并且经由例如合适的电接触件与基于相移的血细胞比容测量块114可操作地进行交互。Strip port connector 106 is configured to operably interface with biosensor 100 , such as an electrochemical-based biosensor configured for determining glucose in a whole blood sample. Accordingly, the biosensor is configured to be operably inserted into the strip port connector 106 and operably interact with the phase-shift based hematocrit measurement block 114 via, for example, suitable electrical contacts.
USB接口108可以是本领域技术人员已知的任何合适的接口。USB接口108基本上为无源部件，其被配置成为手持式测试仪200提供电力并提供数据线。USB interface 108 may be any suitable interface known to those skilled in the art. The USB interface 108 is basically a passive component configured to provide power to the handheld tester 200 and provide data lines.
一旦生物传感器与手持式测试仪200进行交互，或者在进行交互之前，体液样品(例如全血样品)就被引入到生物传感器的样品室中。生物传感器可包含将分析物选择地并且定量地转化到另一种预定化学形式中的酶试剂。例如，生物传感器可包含具有铁氰化物和葡萄糖氧化酶的酶试剂，使得葡萄糖可物理地转化到氧化形式中。Once the biosensor interacts with the hand-held test meter 200, or prior to the interaction, a bodily fluid sample (eg, a whole blood sample) is introduced into the sample chamber of the biosensor. Biosensors may contain enzymatic reagents that selectively and quantitatively convert an analyte into another predetermined chemical form. For example, a biosensor may comprise an enzymatic reagent with ferricyanide and glucose oxidase such that glucose can be physically converted into an oxidized form.
手持式测试仪200的存储器块118包括合适的算法，并且可被配置成连同微控制器块112一起基于生物传感器的电化学响应和所引入的样品的血细胞比容来确定分析物。例如，在分析物血糖的确定中，可使用血细胞比容来补偿血细胞比容对电化学确定的血糖浓度的影响。The memory block 118 of the handheld test meter 200 includes suitable algorithms and can be configured, in conjunction with the microcontroller block 112, to determine an analyte based on the electrochemical response of the biosensor and the hematocrit of the introduced sample. For example, in the determination of the analyte blood glucose, hematocrit can be used to compensate for the effect of hematocrit on the electrochemically determined blood glucose concentration.
微控制器块112设置在外壳内，并且可包括本领域的技术人员已知的任何合适的微控制器和/或微处理器。一种此类合适的微控制器是商购自Texas Instruments(Dallas,TX USA)的部件号为MSP430F5138的微控制器。该微控制器可生成25至250kHz的方波和相同频率的90度相移波，由此用作下文进一步所述的信号生成子块。MSP430F5138还具有适于测量由在本公开的实施方案中采用的基于相移的血细胞比容测量块所生成的电压的模拟-数字(A/D)处理能力。Microcontroller block 112 is disposed within the housing and may include any suitable microcontroller and/or microprocessor known to those skilled in the art. One such suitable microcontroller is commercially available from Texas Instruments (Dallas, TX USA), part number MSP430F5138. The microcontroller can generate a square wave of 25 to 250 kHz and a 90 degree phase shifted wave of the same frequency, thereby serving as a signal generation sub-block as described further below. The MSP430F5138 also has analog-digital (A/D) processing capabilities suitable for measuring voltages generated by the phase-shift based hematocrit measurement blocks employed in embodiments of the present disclosure.
具体参见图2D，基于相移的血细胞比容测量块114包括信号生成子块120、低通滤波器子块122、生物传感器样品池接口子块124、任选的校准加载块126(在图2D的虚线内)、互阻抗放大器子块128、以及相检测器子块130。Referring specifically to FIG. 2D, the phase-shift based hematocrit measurement block 114 includes a signal generation sub-block 120, a low-pass filter sub-block 122, a biosensor sample cell interface sub-block 124, an optional calibration loading block 126 (in FIG. 2D ), the transimpedance amplifier sub-block 128, and the phase detector sub-block 130.
如下文进一步所述，基于相移的血细胞比容测量块114和微控制器块112被配置成通过例如测量驱动穿过体液样品的一个或多个高频电信号的相移来测量插入在手持式测试仪中的生物传感器的样品池中的体液样品的相移。此外，微控制器块112被配置成基于所测量的相移来计算体液的血细胞比容。微控制器块112可通过例如采用A/D转换器测量从相检测器子块接收的电压，将该电压转换到相移中，并且然后采用合适的算法或查找表将相移转换到血细胞比容值中来计算血细胞比容。一旦获悉本公开，本领域技术人员将认识到，此类算法和/或查找表将被配置成考虑到各种因素，诸如条几何形状(包括电极面积和样品室体积)和信号频率。As described further below, the phase-shift based hematocrit measurement block 114 and microcontroller block 112 are configured to measure the phase shift of one or more high-frequency electrical signals inserted in a hand-held Phase shift of a bodily fluid sample in the sample cell of a biosensor in a tester. Furthermore, the microcontroller block 112 is configured to calculate the hematocrit of the bodily fluid based on the measured phase shift. The microcontroller block 112 can convert the voltage into a phase shift by measuring the voltage received from the phase detector sub-block, for example using an A/D converter, and then using a suitable algorithm or lookup table to convert the phase shift into a hematocrit Calculate the hematocrit from the volume value. Once informed of the present disclosure, those skilled in the art will recognize that such algorithms and/or look-up tables will be configured to take into account various factors, such as strip geometry (including electrode area and sample chamber volume) and signal frequency.
已经确定，全血样品的电抗和该样品的血细胞比容之间存在关系。作为并联电容和电阻部件的体液样品(即全血样品)的电模型表明，当交流电(AC)信号被迫使通过体液样品时，AC信号的相移将取决于AC电压的频率和样品的血细胞比容两者。此外，模型表明当信号的频率在约10kHz至25kHz的范围内时血细胞比容对相移具有相对较小的影响，而当信号的频率在约250kHz至500KHz的范围内，并且优选地为约75kHz时血细胞比容对相移具有最大的影响。因此，可通过例如驱动已知频率的AC信号穿过体液样品并且检测其相移来测量体液样品的血细胞比容。例如，频率在10kHz至25kHz范围内信号的相移可用作此类血细胞比容测量中的参考读数，而频率在250kHz至500kHz范围内信号的相移可用作主要测量。It has been determined that there is a relationship between the reactance of a whole blood sample and the hematocrit of that sample. An electrical model of a body fluid sample (i.e., a whole blood sample) as parallel capacitive and resistive components shows that when an alternating current (AC) signal is forced through a body fluid sample, the phase shift of the AC signal will depend on the frequency of the AC voltage and the hematocrit of the sample accommodate both. Furthermore, the model shows that hematocrit has relatively little effect on the phase shift when the frequency of the signal is in the range of about 10 kHz to 25 kHz, while when the frequency of the signal is in the range of about 250 kHz to 500 KHz, and preferably about 75 kHz When the hematocrit has the greatest effect on the phase shift. Thus, the hematocrit of a body fluid sample can be measured, for example, by driving an AC signal of known frequency through the body fluid sample and detecting its phase shift. For example, the phase shift of a signal with a frequency in the range of 10kHz to 25kHz can be used as a reference reading in such hematocrit measurements, while the phase shift of a signal with a frequency in the range of 250kHz to 500kHz can be used as the primary measurement.
图3A为测试条100的示例性分解透视图，其可包括设置在衬底5上的七个层。设置在衬底5上的七个层可为第一导电层50(其还可称为电极层50)、绝缘层16、两个重叠的试剂层22a和22b、包括粘合剂部分24、26和28的粘合剂层60、亲水层70和形成测试条100的覆盖件94的顶层80。测试条100可通过一系列步骤来制造，其中利用例如丝网印刷工艺来将导电层50、绝缘层16、试剂层22和粘合剂层60依次沉积在衬底5上。需注意，电极10、12和14被设置成用于与试剂层22a和22b接触，而物理特性感测电极19a和20a为间隔开的并且不与试剂层22接触。亲水层70和顶层80可自卷材设置并层合到衬底5上，作为一体式层合物或者作为单独的层。如图3A所示，测试条100具有远侧部分3和近侧部分4。FIG. 3A is an exemplary exploded perspective view of test strip 100 , which may include seven layers disposed on substrate 5 . The seven layers provided on the substrate 5 may be a first conductive layer 50 (which may also be referred to as an electrode layer 50), an insulating layer 16, two overlapping reagent layers 22a and 22b, including adhesive portions 24, 26 Adhesive layer 60 and 28, hydrophilic layer 70 and top layer 80 forming cover 94 of test strip 100. The test strip 100 can be manufactured in a series of steps in which the conductive layer 50, the insulating layer 16, the reagent layer 22 and the adhesive layer 60 are sequentially deposited on the substrate 5 using, for example, a screen printing process. Note that electrodes 10 , 12 and 14 are provided for contacting reagent layers 22 a and 22 b , while physical property sensing electrodes 19 a and 20 a are spaced apart and not in contact with reagent layer 22 . The hydrophilic layer 70 and top layer 80 can be provided from a web and laminated to the substrate 5, either as an integral laminate or as separate layers. As shown in FIG. 3A , test strip 100 has a distal portion 3 and a proximal portion 4 .
测试条100可包括其中可吸取或沉积生理流体样品95的样品接收室92(图3B)。本文所讨论的生理流体样品可为血液。样品接收室92可包括在近侧端部处的入口和在测试条100的侧边缘处的出口，如图3A所示。流体样品95可沿着轴线L-L(图3B)施加至入口以填充样品接收室92，使得能够测量葡萄糖。位于试剂层22附近的第一粘结垫24和第二粘结垫26的侧边缘各自限定样品接收室92的壁，如图3A所示。样品接收室92的底部部分或者“底板”可包括衬底5、导电层50和绝缘层16的一部分，如图3A所示。样品接收室92的顶部部分或者“顶板”可包括远侧亲水部分32，如图3A所示。对于测试条100，如图3A所示，衬底5可用作有助于支撑随后所施加的层的基底。衬底5可为聚酯片的形式，诸如聚对苯二甲酸乙二醇酯(PET)材料(由Mitsubishi供应的Hostaphan PET)。衬底5可以为卷形式，标称350微米厚乘370毫米宽乘大约60米长。The test strip 100 can include a sample receiving chamber 92 (FIG. 3B) into which a physiological fluid sample 95 can be aspirated or deposited. The physiological fluid sample discussed herein may be blood. Sample receiving chamber 92 may include an inlet at the proximal end and an outlet at the side edge of test strip 100, as shown in FIG. 3A. A fluid sample 95 may be applied to the inlet along axis L-L (FIG. 3B) to fill the sample receiving chamber 92, enabling glucose to be measured. The side edges of the first adhesive pad 24 and the second adhesive pad 26 located adjacent the reagent layer 22 each define a wall of a sample receiving chamber 92, as shown in FIG. 3A. The bottom portion or "floor" of the sample receiving chamber 92 may include a portion of the substrate 5, the conductive layer 50 and the insulating layer 16, as shown in FIG. 3A. The top portion, or "ceiling," of sample receiving chamber 92 may include distal hydrophilic portion 32, as shown in FIG. 3A. For test strip 100, as shown in Figure 3A, substrate 5 may serve as a base to help support subsequently applied layers. Substrate 5 may be in the form of a polyester sheet, such as polyethylene terephthalate (PET) material (Hostaphan PET supplied by Mitsubishi). Substrate 5 may be in roll form, nominally 350 microns thick by 370 mm wide by approximately 60 meters long.
导电层被用来形成可用于对葡萄糖进行电化学测量的电极。第一导电层50可由丝网印刷到衬底5上的碳素墨制成。在丝网印刷工艺中，将碳素墨加载到丝网上，然后利用刮墨刀将碳素墨透过丝网转印。印刷的碳素墨可利用约140℃的热空气进行干燥。碳素墨可包括VAGH树脂、碳黑、石墨(KS15)和用于该树脂、碳和石墨混合物的一种或多种溶剂。更具体地，碳素墨可在碳素墨中包含比率为约2.90:1的碳黑:VAGH树脂、以及比率为约2.62:1的石墨:碳黑。The conductive layer is used to form electrodes that can be used for electrochemical measurements of glucose. The first conductive layer 50 may be made of carbon ink screen printed onto the substrate 5 . In the screen printing process, carbon ink is loaded onto the screen, and then the carbon ink is transferred through the screen with a squeegee. The printed carbon ink can be dried with hot air at about 140°C. Carbon ink may include VAGH resin, carbon black, graphite (KS15) and one or more solvents for the resin, carbon and graphite mixture. More specifically, the carbon ink may include carbon black:VAGH resin in a ratio of about 2.90:1, and graphite:carbon black in a ratio of about 2.62:1 in the carbon ink.
如图3A所示，对于测试条100，第一导电层50可包括参考电极10、第一工作电极12、第二工作电极14、第三物理特性感测电极和第四物理特性感测电极19a和19b、第一接触垫13、第二接触垫15、参考接触垫11、第一工作电极轨道8、第二工作电极轨道9、参比电极轨道7、和条检测棒17。物理特性感测电极19a和20a设置有相应的电极轨道19b和20b。导电层可由碳素墨形成。第一接触垫13、第二接触垫15和参考接触垫11可适于电连接至测试仪。第一工作电极轨道8提供从第一工作电极12到第一接触垫13的电连续通路。相似地，第二工作电极轨道9提供从第二工作电极14至第二接触垫15的电连续通路。相似地，参考电极轨道7提供从参考电极10至参考接触垫11的电连续通路。条检测棒17电连接至参考接触垫11。第三电极轨道和第四电极轨道19b和20b连接到相应的电极19a和20a。测试仪可通过测量参考接触垫11和条检测棒17之间的导通来检测测试条100已被正确插入，如图3A所示。As shown in FIG. 3A, for a test strip 100, the first conductive layer 50 may include a reference electrode 10, a first working electrode 12, a second working electrode 14, a third physical property sensing electrode and a fourth physical property sensing electrode 19a and 19b, first contact pad 13, second contact pad 15, reference contact pad 11, first working electrode track 8, second working electrode track 9, reference electrode track 7, and bar detection rod 17. The physical property sensing electrodes 19a and 20a are provided with corresponding electrode tracks 19b and 20b. The conductive layer may be formed of carbon ink. The first contact pad 13, the second contact pad 15 and the reference contact pad 11 may be adapted to be electrically connected to a tester. The first working electrode track 8 provides an electrically continuous path from the first working electrode 12 to the first contact pad 13 . Similarly, the second working electrode track 9 provides an electrically continuous path from the second working electrode 14 to the second contact pad 15 . Similarly, reference electrode track 7 provides an electrically continuous path from reference electrode 10 to reference contact pad 11 . The strip detection stick 17 is electrically connected to the reference contact pad 11 . The third and fourth electrode tracks 19b and 20b are connected to respective electrodes 19a and 20a. The tester can detect that the test strip 100 has been inserted correctly by measuring the continuity between the reference contact pad 11 and the strip detection bar 17, as shown in FIG. 3A.
在图3B的实施方案(其为图3A的测试条的变型)中，提供附加电极10a作为多个电极19a、20a、14、12和10中的任一个的延长。必须注意的是，内置式屏蔽或接地电极10a用于降低或消除用户手指或身体和特性测量电极19a和20a之间的任何电容耦合。接地电极10a允许任何电容背离感测电极19a和20a。为此，可将接地电极10a连接至其它五个电极中的任一个电极或连接至其自身的单独接触垫(和轨道)，该单独接触垫(和轨道)用于连接至测量仪上的地而非经由相应的轨道7、8和9连接至接触垫15、17、13中的一个或多个。在优选的实施方案中，接地电极10a连接至其上设置有试剂22的三个电极中的一个电极。在最优选的实施方案中，接地电极10a连接至电极10。作为接地电极，有利的是将接地电极连接至参考电极(10)，以便不对工作电极测量产生任何附加电流，该附加电流可来自样品中的背景干扰化合物。此外通过将屏蔽或接地电极10a连接至电极10，据信能有效地增加反电极10的尺寸，该尺寸尤其在高信号情况下可成为限制性的。在图3B的实施方案中，试剂被布置为使得其不与测量电极19a和20a接触。另选地，试剂22可被布置为使得试剂22接触感测电极19a和20a中的至少一个感测电极。In the embodiment of FIG. 3B , which is a variation of the test strip of FIG. 3A , an additional electrode 10a is provided as an extension of any one of the plurality of electrodes 19a , 20a , 14 , 12 and 10 . It must be noted that the built-in shield or ground electrode 10a serves to reduce or eliminate any capacitive coupling between the user's finger or body and the characteristic measurement electrodes 19a and 20a. Ground electrode 10a allows any capacitance away from sense electrodes 19a and 20a. To do this, ground electrode 10a can be connected to any of the other five electrodes or to its own separate contact pad (and rail) for connection to ground on the meter Instead of connecting to one or more of the contact pads 15 , 17 , 13 via the respective tracks 7 , 8 and 9 . In a preferred embodiment, the ground electrode 10a is connected to one of the three electrodes on which the reagent 22 is disposed. In the most preferred embodiment, the ground electrode 10a is connected to the electrode 10 . As a ground electrode, it is advantageous to connect the ground electrode to the reference electrode (10) so as not to generate any additional current to the working electrode measurement, which may come from background interfering compounds in the sample. Furthermore, by connecting the shielding or ground electrode 10a to the electrode 10, it is believed that the size of the counter electrode 10 can be effectively increased, which can become limiting especially in high signal situations. In the embodiment of Figure 3B, the reagent is arranged such that it does not come into contact with the measurement electrodes 19a and 20a. Alternatively, the reagent 22 may be arranged such that the reagent 22 contacts at least one of the sensing electrodes 19a and 20a.
在测试条100的另选的型式中，如此处在图3C所示，顶层38、亲水膜层34和垫片29已结合在一起以形成一体式组件，该一体式组件用于安装到具有靠近绝缘层16’设置的试剂层22’的衬底5。In an alternative version of the test strip 100, as shown here in FIG. Substrate 5 with reagent layer 22' disposed adjacent to insulating layer 16'.
在图3B的实施方案中，分析物测量电极10、12和14设置成与图3A大致相同的构型。然而，来感测物理特性(例如，血细胞比容)水平的电极19a和20a设置成间隔开的构型，其中一个电极19a靠近测试腔室92的入口92a并且另一个电极20a位于测试腔室92的相对末端。电极10、12和14设置成与试剂层22接触，而电极19a和20a不与试剂接触。In the embodiment of FIG. 3B, the analyte measuring electrodes 10, 12 and 14 are arranged in substantially the same configuration as in FIG. 3A. However, the electrodes 19a and 20a to sense the level of a physical characteristic (e.g., hematocrit) are arranged in a spaced apart configuration, with one electrode 19a proximate the entrance 92a of the test chamber 92 and the other electrode 20a located in the test chamber 92 opposite end of . The electrodes 10, 12 and 14 are arranged in contact with the reagent layer 22, while the electrodes 19a and 20a are not in contact with the reagent.
在图3A-图3C中，物理特性(例如，血细胞比容)感测电极19a和20a设置为彼此相邻，并且可放置在测试腔室92的入口92a的相对末端92b处(图3C和图3D)或邻近入口92a处(为简明起见未示出)。在所有这些实施方案中，物理特性感测电极与试剂层22间隔开，使得这些物理特性感测电极在包含葡萄糖的流体样品(例如，血液、对照溶液或间质液)存在的情况下不受试剂的电化学反应的影响。In FIGS. 3A-3C , physical property (e.g., hematocrit) sensing electrodes 19a and 20a are disposed adjacent to each other and may be placed at opposite ends 92b of inlet 92a of test chamber 92 (FIG. 3C and FIG. 3D) or near the entrance 92a (not shown for simplicity). In all of these embodiments, the physical property sensing electrodes are spaced apart from the reagent layer 22 such that they are not affected in the presence of a glucose-containing fluid sample (e.g., blood, control solution, or interstitial fluid). The influence of the electrochemical reaction of reagents.
在生物传感器的各种实施方案中，对沉积在生物传感器上的流体样品进行了两种测量。一种测量为流体样品中的分析物(例如，葡萄糖)的浓度的测量，而另一种测量为相同样品的物理特性(例如，血细胞比容)的测量。物理特性(例如，血细胞比容)的测量用于修正或校正葡萄糖测量，以便移除或降低红血细胞对葡萄糖测量的影响。两个测量(葡萄糖和血细胞比容)可在持续时间内按照顺序、同时地、或重叠地进行。例如，可首先进行葡萄糖测量，然后进行物理特性(例如，血细胞比容)测量；首先进行物理特性(例如，血细胞比容)测量，然后进行葡萄糖测量；两个测量同时进行；或者一个测量的持续时间可与另一个测量的持续时间重叠。下文中参考图4A、图4B和图5来详细地论述每个测量。In various embodiments of the biosensor, two measurements are made on the fluid sample deposited on the biosensor. One measurement is a measurement of the concentration of an analyte (eg, glucose) in a fluid sample, while the other measurement is a measurement of a physical property of the same sample (eg, hematocrit). Measurements of physical properties (eg, hematocrit) are used to correct or correct glucose measurements in order to remove or reduce the influence of red blood cells on the glucose measurements. The two measurements (glucose and hematocrit) can be performed sequentially, simultaneously, or overlappingly over a duration. For example, a glucose measurement can be taken first, followed by a physical property (e.g., hematocrit) measurement; a physical property (e.g., hematocrit) measurement can be taken first, followed by a glucose measurement; both measurements taken simultaneously; or a continuous A time can overlap the duration of another measurement. Each measurement is discussed in detail below with reference to FIGS. 4A , 4B and 5 .
图4A为施加至测试条100及其变型(此处示于图3A-图3C中)的测试信号的示例性图表。在将流体样品施加至测试条100(或其变型)之前，测试仪200处于流体检测模式，其中在第二工作电极和参考电极之间施加约400毫伏的第一测试信号。优选地同时在第一工作电极(例如，条100的电极12)和参考电极(例如，条100的电极10)之间施加约400毫伏的第二测试信号。另选地，还可同时施加第二测试信号，使得施加第一测试信号的时间间隔与施加第二测试电压的时间间隔重叠。在起始时间为零处检测到生理流体之前的流体检测时间间隔TFD期间，测试仪可处于流体检测模式。在流体检测模式中，测试仪200确定流体何时被施加至测试条100(或其变体)，使得流体润湿相对于参考电极10的第一工作电极12或第二工作电极14(或者这两个电极)。一旦测试仪200由于例如在第一工作电极12或第二工作电极14中的一者或两者处测量的测试电流充分增大而识别出生理流体已施加，则测试仪200在零时刻“0”处分配为零的第二标记，并启动测试时间间隔TS。测试仪200可以合适的取样速率，诸如，例如，每隔1毫秒至每隔100毫秒来对电流瞬态输出进行取样。在测试时间间隔TS结束时，移除测试信号。为简单起见，图4A仅示出施加至测试条100(或其变体)的第一测试信号。FIG. 4A is an exemplary graph of test signals applied to test strip 100 and variations thereof (shown here in FIGS. 3A-3C ). Prior to applying a fluid sample to test strip 100 (or a variation thereof), test meter 200 is in a fluid detection mode in which a first test signal of approximately 400 millivolts is applied between the second working electrode and the reference electrode. A second test signal of approximately 400 millivolts is preferably applied simultaneously between the first working electrode (eg, electrode 12 of strip 100 ) and the reference electrode (eg, electrode 10 of strip 100 ). Alternatively, the second test signal can also be applied simultaneously, so that the time interval of applying the first test signal overlaps with the time interval of applying the second test voltage. During the fluid detection time interval TFD before physiological fluid is detected at start time zero, the test meter may be in the fluid detection mode. In the fluid detection mode, the test meter 200 determines when a fluid is applied to the test strip 100 (or a variation thereof) such that the fluid wets either the first working electrode 12 or the second working electrode 14 relative to the reference electrode 10 (or this two electrodes). Once the tester 200 recognizes that a physiological fluid has been applied due to, for example, a sufficient increase in the test current measured at one or both of the first working electrode 12 or the second working electrode 14, the tester 200 at time zero "0 ” is assigned a second marker of zero and starts the test interval TS . The tester 200 may sample the current transient output at a suitable sampling rate, such as, for example, every 1 millisecond to every 100 milliseconds. At the end of the test time interval TS the test signal is removed. For simplicity, FIG. 4A only shows the first test signal applied to test strip 100 (or a variation thereof).
在下文中，描述了如何从已知的信号瞬态(例如，作为时间函数的以纳安计的测量电信号响应)来确定分析物(例如，葡萄糖)浓度，该信号瞬态是在将图4A的测试电压施加至测试条100(或其变体)时测量的。In the following, it is described how to determine the analyte (e.g., glucose) concentration from a known signal transient (e.g., a measured electrical signal response in nanoamperes as a function of time), which is presented in Figure 4A is measured when the test voltage is applied to the test strip 100 (or a variation thereof).
在图4A中，施加至测试条100(或本文所述的变体)的第一测试电压和第二测试电压通常为约+100毫伏至约+600毫伏。在其中电极包括碳素墨并且介体包括铁氰化物的一个实施方案中，测试信号为约+400毫伏。其它介体和电极材料组合将需要不同的测试电压，如本领域技术人员已知的。测试电压的持续时间通常为反应期后约1至约5秒，并且通常为反应期后约3秒。通常，测试序列时间TS是相对于时间t0测量的。当电压401被保持图4A中TS的持续时间时，产生如此处在图4B所示的输出信号，其中第一工作电极12的电流瞬态702始于零时刻处产生，同样第二工作电极14的电流瞬态704也相对于零时刻产生。应当指出的是，尽管信号瞬态702和704已放置在相同的参考零点上以用于解释该方法的目的，但在物理条件下，两个信号之间存在微小的时间差，这是因为腔室内的流体沿着轴线L-L朝向工作电极12和14中的每个工作电极。然而，将电流瞬态在微控制器中进行取样和配置以具有相同的开始时间。在图4B中，电流瞬态在靠近峰时刻Tp时积聚到峰，此时电流缓慢地下降直至接近零时刻之后2.5秒或5秒中的一者。在大约5秒时的点706处，可测量工作电极12和14中的每个电极的输出信号并且将它们进行加和。另选地，可将得自工作电极12和14中的仅一者的信号进行翻倍。In FIG. 4A, the first and second test voltages applied to test strip 100 (or a variation described herein) are typically about +100 millivolts to about +600 millivolts. In one embodiment where the electrode comprises carbon ink and the mediator comprises ferricyanide, the test signal is about +400 millivolts. Other mediator and electrode material combinations will require different test voltages, as known to those skilled in the art. The duration of the test voltage is typically about 1 to about 5 seconds after the reaction period, and typically about 3 seconds after the reaction period. Typically, the test sequence time TS is measured relative to time t0 . When the voltage 401 is maintained for the duration ofTS in FIG. 4A, an output signal as shown here in FIG. 4B is produced, wherein the current transient 702 of the first working electrode 12 is generated starting at time zero, and likewise the second working electrode A current transient 704 of 14 is also generated relative to time zero. It should be noted that although the signal transients 702 and 704 have been placed at the same reference zero point for the purpose of explaining the method, under physical conditions there is a slight time difference between the two signals due to the The fluid is directed toward each of working electrodes 12 and 14 along axis LL. However, the current transients are sampled and configured in the microcontroller to have the same start time. In FIG. 4B , the current transient builds up to a peak near the peak instant Tp, at which point the current slowly decreases until one of 2.5 seconds or 5 seconds after near zero instant. At point 706 at approximately 5 seconds, the output signal of each of working electrodes 12 and 14 may be measured and summed. Alternatively, the signal from only one of working electrodes 12 and 14 may be doubled.
重新参见图2B，系统驱动信号以测量或取样在多个时间点或位置T1、T2、T3、…TN中的任一个处得自至少一个工作电极(12和14)的输出信号IE。如在图4B中可见，时间位置可为测试序列TS中的任何时间点或时间间隔。例如，测量输出信号的时间位置可为1.5秒处的单个时间点T1.5或与靠近2.8秒的时间点T2.8重叠的间隔708(例如，～10毫秒间隔或更长间隔，这取决于系统的取样速率)。Referring back to FIG. 2B, the system drives the signal to measure or sample the output signal I from at least one of the working electrodes (12 and 14) at anyone of a plurality of time points or positions T1, T2, T3, ...TN .E. As can be seen in Fig. 4B, the time location may be any time point or time interval in the test sequence TS. For example, the temporal location of the measured output signal may be a single time point T1.5 at 1.5 seconds or an interval 708 overlapping time point T2.8 near 2.8 seconds (e.g., ~10 millisecond intervals or longer, depending on the system's sampling rate).
基于特定测试条100及其变型的生物传感器的参数(例如，批校准代码偏移和批斜率)的知识，可计算分析物(例如，葡萄糖)的浓度。在测试序列期间，可对输出瞬态702和704进行取样，以导出多个时间位置处的信号IE(通过对电流IWE1和IWE2中的每一者进行加和或者对IWE1或IWE2中的一者进行翻倍)。基于特定测试条100的批校准代码偏移和批斜率的知识，可以计算分析物(例如，葡萄糖)浓度。Based on knowledge of the parameters (eg, batch calibration code offset and batch slope) of the particular test strip 100 and its variant biosensors, the concentration of the analyte (eg, glucose) can be calculated. During the test sequence, the output transients 702 and 704 can be sampled to derive the signal IE at multiple time locations (either by summing each of the currents IWE1 and IWE2 or by summing either IWE1 or I WE1 one ofWE2 for doubling). Based on knowledge of the batch calibration code offset and batch slope for a particular test strip 100, the analyte (eg, glucose) concentration can be calculated.
应该指出的是，“截距”和“斜率”是通过测量一批生物传感器的校准数据而获得的值。通常从该组或批中随机选择1500个左右的生物传感器。来自供体的生理流体(例如，血液)被分类为多种分析物水平：通常6种不同的葡萄糖浓度。通常，来自12个不同供体的血液被分类为六种水平中的每个水平。对来自相同供体和水平的血液给予八个生物传感器(或本实施方案中的条)，使得针对该组总共进行12×6×8＝576个测试。通过使用标准实验室分析器，诸如Yellow Springs Instrument(YSI)测量这些条，并且以实际分析物水平(例如血糖浓度)为基准。测量出的葡萄糖浓度的曲线图相对于实际葡萄糖浓度(或测量出的电流对YSI电流)绘制，并且按公式y＝mx+c最小二乘拟合成该曲线图，以针对该组或批中剩余的条赋值给批斜率m和批截距c。申请人还已提供其中在分析物浓度的确定期间导出批斜率的方法和系统。“批斜率”或“斜率”可因此被限定为针对相对于实际葡萄糖浓度(或测量的电流对YSI电流)绘制的测量葡萄糖浓度的图进行最佳拟合的线的测量或导出的斜率。“批截距”或“截距”可因此被限定为针对相对于实际葡萄糖浓度(或测量的电流对YSI电流)绘制的测量葡萄糖浓度的图进行最佳拟合的线与y轴相交的点。It should be noted that "intercept" and "slope" are values obtained by measuring calibration data of a batch of biosensors. Typically 1500 or so biosensors are randomly selected from this set or batch. Physiological fluid (eg, blood) from a donor is classified into various analyte levels: typically 6 different glucose concentrations. Typically, blood from 12 different donors is classified for each of six levels. Eight biosensors (or strips in this embodiment) are administered blood from the same donor and level, making a total of 12 x 6 x 8 = 576 tests for the set. The strips are measured by using a standard laboratory analyzer, such as the Yellow Springs Instrument (YSI), and are based on actual analyte levels (eg, blood glucose concentrations). A graph of measured glucose concentration is plotted against actual glucose concentration (or measured current versus YSI current) and the graph is least squares fitted to the graph for the group or batch The remaining bars are assigned to batch slope m and batch intercept c. Applicants have also provided methods and systems in which batch slopes are derived during determination of analyte concentrations. "Batch slope" or "slope" may thus be defined as the measured or derived slope of the line that best fits a plot of measured glucose concentration against actual glucose concentration (or measured current versus YSI current). "Batch intercept" or "intercept" may thus be defined as the point at which the line of best fit for a plot of measured glucose concentration plotted against actual glucose concentration (or measured current versus YSI current) intersects the y-axis .
前面所述的各种部件、系统和规程允许申请人提供分析物测量系统。具体地，此系统包括具有衬底和多个电极的生物传感器，所述多个电极连接至相应的电极连接器。该系统还包括分析物测量仪200，该分析物测量仪200具有外壳、被配置成连接至测试条的相应电极连接器的测试条端口连接器以及微控制器300，此处如图2B中所示。微控制器300与测试条端口连接器220电连通以施加电信号或感测来自多个电极的电信号。The various components, systems, and procedures described above allow Applicants to provide an analyte measurement system. Specifically, the system includes a biosensor having a substrate and a plurality of electrodes connected to corresponding electrode connectors. The system also includes an analyte meter 200 having a housing, a test strip port connector configured to connect to a corresponding electrode connector of a test strip, and a microcontroller 300, here shown in FIG. 2B Show. Microcontroller 300 is in electrical communication with test strip port connector 220 to apply electrical signals or sense electrical signals from a plurality of electrodes.
参见图2B，示出了测量仪200的优选具体实施的细节，其中图2A和图2B中的相同数字具有共同的描述。在图2B中，测试条端口连接器220通过五条线连接至模拟接口306，该五条线包括阻抗感测线EIC(用以接收来自物理特性感测电极的信号)、交变信号线AC(用以将信号驱动至物理特性感测电极)、参考电极的基准线、以及相应工作电极1和工作电极2的信号感测线。还可为连接器220提供条检测线221以指示测试条的插入。模拟接口306为处理器300提供四个输入：(1)阻抗实部Z’；(2)阻抗虚部Z”；(3)从生物传感器的工作电极1取样或测量的信号或者Iwe1；(4)从生物传感器的工作电极2取样或测量的信号或者Iwe2。存在从处理器300到接口306的一个输出，以将具有25kHz至约250kHz之间的任一值或更大值的振荡信号AC驱动至物理特性感测电极。可从阻抗实部Z’和阻抗虚部Z”来确定相位差P(以度为单位)，其中：Referring to Figure 2B, details of a preferred implementation of the gauge 200 are shown, where like numerals in Figures 2A and 2B have a common description. In FIG. 2B , the test strip port connector 220 is connected to the analog interface 306 by five lines, including an impedance sensing line EIC (to receive signals from physical characteristic sensing electrodes), an alternating signal line AC (to use to drive signals to the physical property sensing electrode), the reference line for the reference electrode, and the signal sense lines for the corresponding working electrode 1 and working electrode 2. A strip test line 221 may also be provided to connector 220 to indicate insertion of a test strip. The analog interface 306 provides four inputs to the processor 300: (1) the real part of the impedance Z'; (2) the imaginary part of the impedance Z"; (3) the signal sampled or measured from the working electrode 1 of the biosensor orIwe1 ; 4) The signal orIwe2 sampled or measured from the working electrode 2 of the biosensor. There is one output from the processor 300 to the interface 306 to convert an oscillating signal having any value between 25kHz to about 250kHz or greater AC drive to the physical property sensing electrodes. The phase difference P (in degrees) can be determined from the impedance real part Z' and the impedance imaginary part Z", where:
P＝tan-1{Z”/Z’} 公式3.1P=tan-1 {Z”/Z’} Formula 3.1
并且可从接口306的线Z’和Z”来确定量值M(以欧姆表示并且通常写为│Z│)，其中：And the magnitude M (expressed in ohms and usually written as │Z│) can be determined from lines Z' and Z" of the interface 306, where:
在该系统中，微处理器被配置成：(a)将第一信号施加至多个电极，使得导出由流体样品的物理特性限定的批斜率以及(b)将第二信号施加至多个电极，使得基于所导出的批斜率来确定分析物浓度。对于该系统而言，测试条或生物传感器的多个电极包括用于测量物理特性的至少两个电极和用于测量分析物浓度的至少两个其他电极。例如，所述至少两个电极和所述至少两个其它电极设置在提供于衬底上的相同的腔室中。另选地，所述至少两个电极和所述至少两个其它电极设置在提供于衬底上的相应的两个不同腔室中。应该指出的是，对于一些实施方案，全部电极均设置在由衬底限定的相同平面上。具体地，在本文所述实施方案的一些实施方案中，将试剂靠近至少两个其它电极设置，并且不将试剂设置在至少两个电极上。该系统中值得注意的一个特征在于如下能力，即在将流体样品(其可为生理样品)沉积到生物传感器上约10秒内提供准确分析物测量以作为测试序列的部分。In this system, the microprocessor is configured to: (a) apply a first signal to the plurality of electrodes such that a batch slope defined by the physical properties of the fluid sample is derived and (b) apply a second signal to the plurality of electrodes such that Analyte concentrations are determined based on the derived batch slopes. For the system, the plurality of electrodes of the test strip or biosensor includes at least two electrodes for measuring a physical property and at least two other electrodes for measuring analyte concentration. For example, said at least two electrodes and said at least two other electrodes are arranged in the same chamber provided on the substrate. Alternatively, said at least two electrodes and said at least two other electrodes are arranged in respective two different chambers provided on the substrate. It should be noted that for some embodiments, all electrodes are disposed on the same plane defined by the substrate. Specifically, in some of the embodiments described herein, the reagent is disposed proximate to at least two other electrodes, and the reagent is not disposed on at least two electrodes. One notable feature of this system is the ability to provide accurate analyte measurements as part of a test sequence within about 10 seconds of depositing a fluid sample (which may be a physiological sample) onto the biosensor.
作为条100(图3A-图3C)的分析物计算(例如，葡萄糖)的示例，在图4B中假定，第一工作电极12在706处的取样信号值为约1600纳安，而第二工作电极14在706处的信号值为约1300纳安，并且测试条的校准代码指示截距为约500纳安并且斜率为约18nA/mg/dL。然后可从以下公式3.3确定葡萄糖浓度G0：As an example of an analyte calculation (e.g., glucose) for strip 100 (FIGS. 3A-3C), it is assumed in FIG. The signal value of electrode 14 at 706 is about 1300 nanoampere, and the calibration code of the test strip indicates an intercept of about 500 nanoampere and a slope of about 18 nA/mg/dL. The glucose concentration G0 can then be determined from Equation 3.3 below:
G0＝[(IE)-截距]/斜率 公式3.3G0 = [(IE )-intercept]/slope Formula 3.3
其中in
IE为如下信号(与分析物浓度成比例)，该信号为得自生物传感器中的所有电极的总信号(例如，对于传感器100而言，得自两个电极12和14(或者Iwe1+Iwe2))；IE is the signal (proportional to the analyte concentration) that is the total signal from all electrodes in the biosensor (e.g., for sensor 100, from both electrodes 12 and 14 (orIwe1 + Iwe2 ));
Iwe1为在设置取样时间处针对第一工作电极测量的信号；Iwe1 is the signal measured for the first working electrode at the set sampling time;
Iwe2为在设置取样时间处针对第二工作电极测量的信号；Iwe2 is the signal measured for the second working electrode at the set sampling time;
斜率为从该特定测试条所在的一批测试条的校准测试中获得的值；The slope is the value obtained from a calibration test of the batch of test strips in which this particular test strip is located;
截距为从该特定测试条所在的一批测试条的校准测试中获得的值。The intercept is the value obtained from the calibration test of the batch of test strips in which that particular test strip was included.
根据公式3.3；得出G0＝[(1600+1300)-500]/18，因此，G0＝133.33纳安，约133mg/dL。According to formula 3.3; G0 =[(1600+1300)-500]/18, therefore, G0 =133.33 nanoampere, about 133 mg/dL.
此处应当指出的是，尽管已相对于具有两个工作电极(图3A中的12和14)的生物传感器100给出示例，使得已将得自相应工作电极的所测量的电流加在一起以提供总测量电流IE，但在其中仅存在一个工作电极(电极12或电极14)的测试条100的变型中，可将得自两个工作电极中的仅一个电极的信号乘以2。除了总信号之外，可将得自每个工作电极的信号的平均值用作本文所述的公式3.3、6、和5-7的总测量电流IE，当然，需要对运算系数进行适当的修正(这对于本领域的技术人员而言是已知的)，相比于其中将测量信号加在一起的实施方案，以补偿较低的总测量电流IE。另选地，可将测量信号的平均值乘以2并且用作公式3.3、6和5-7中的IE，且无需如先前的示例那样来导出运算系数。应当指出的是，此处未针对任何物理特性(例如，血细胞比容值)来校正分析物(例如，葡萄糖)浓度，并且可将一定的偏移提供到信号值Iwe1和Iwe2以补偿测量仪200的电路中的错误或延迟时间。还可以用温度补偿确保将结果校准至参考温度，诸如例如约20℃的室温。It should be noted here that although the example has been given with respect to a biosensor 100 having two working electrodes (12 and 14 in FIG. 3A ), such that the measured currents from the respective working electrodes have been added together to obtain The total measured currentIE is provided, but in variations of test strip 100 in which only one working electrode (either electrode 12 or electrode 14) is present, the signal from only one of the two working electrodes may be multiplied by two. In addition to the total signal, the average value of the signal from each working electrode can be used as the total measured current IE for Equations 3.3, 6, and 5-7 described herein, with appropriate adjustments to the operational coefficients, of course. Correction, which is known to a person skilled in the art, to compensate for the lower total measured current IE compared to an embodiment in which the measured signals are added together. Alternatively, the mean value of the measured signal can be multiplied by 2 and used as IE in equations 3.3, 6 and5-7 , without deriving operational coefficients as in the previous example. It should be noted that here the analyte (e.g. glucose) concentration is not corrected for any physical characteristic (e.g. hematocrit value) and a certain offset may be provided to the signal valuesIwe1 andIwe2 to compensate the measurement errors or delays in the circuitry of the meter 200. Temperature compensation may also be used to ensure that the results are calibrated to a reference temperature, such as eg room temperature of about 20°C.
既然可根据信号IE来确定分析物(例如，葡萄糖)浓度(G0)，则在下文中提供了对用以确定流体样品的物理特性(例如，血细胞比容)的申请人的技术的描述。具体地，系统200(图2a和图2b)将第一频率(例如，约25-500千赫)下的第一振荡输入信号施加至一对感测电极。该系统还被设置以测量或检测来自第三电极和第四电极的第一振荡输出信号802，这具体地涉及测量第一输入振荡信号和第一输出振荡信号之间的第一时间差Δt1。在相同时间或在重叠的时间段期间，所述系统还可将第二频率(例如，约100千赫至约1兆赫或更高，并且优选地为约250千赫)下的第二振荡输入信号(为简明起见未示出)施加至一对电极，并且随后测量或检测来自第三电极和第四电极的第二振荡输出信号，这可涉及测量第一输入振荡信号和第一输出振荡信号之间的第二时间差Δt2(未示出)。从这些信号中，系统基于第一时间差和第二时间差Δt1和Δt2来估计流体样品的物理特性(例如，血细胞比容)。其后，所述系统能够导出葡萄糖浓度。可通过应用如下形式的公式来完成物理特性(例如，血细胞比容)的估计：Now that analyte (eg, glucose) concentration (G0 ) can be determined from signalIE , a description of Applicants' technique to determine a physical characteristic (eg, hematocrit) of a fluid sample is provided below. Specifically, system 200 (FIGS. 2a and 2b) applies a first oscillating input signal at a first frequency (eg, about 25-500 kHz) to a pair of sensing electrodes. The system is also arranged to measure or detect a first oscillating output signal 802 from the third and fourth electrodes, which in particular involves measuring a first time difference Δt1 between the first input oscillating signal and the first output oscillating signal. The system may also input a second oscillation at a second frequency (e.g., about 100 kHz to about 1 MHz or higher, and preferably about 250 kHz) at the same time or during overlapping time periods. A signal (not shown for simplicity) is applied to a pair of electrodes, and then measuring or detecting a second oscillating output signal from the third and fourth electrodes, which may involve measuring the first input oscillating signal and the first output oscillating signal The second time difference Δt2 (not shown). From these signals, the system estimates a physical property of the fluid sample (eg, hematocrit) based on the first and second time differences Δt1 and Δt2 . Thereafter, the system is able to derive the glucose concentration. Estimation of a physical property (eg, hematocrit) can be accomplished by applying a formula of the form:
其中in
C1、C2和C3中的每个均为测试条的运算常数，并且Each of C1 , C2 and C3 is an operational constant of the test strip, and
m1表示得自回归数据的参数。m1 denotes a parameter obtained from the regression data.
该示例性技术的详细内容可见于2011年9月2日提交的名称为“HematocritCorrected Glucose Measurements for Electrochemical Test Strip Using TimeDifferential ofthe Signals”的美国临时专利申请S.N.61/530,795(代理人案卷号DDI-5124USPSP)中，该专利以引用方式并入本文。Details of this exemplary technique can be found in U.S. Provisional Patent Application S.N.61/530,795, entitled "HematocritCorrected Glucose Measurements for Electrochemical Test Strip Using TimeDifferential of the Signals," filed September 2, 2011 (Attorney Docket No. DDI-5124USPSP) , which is incorporated herein by reference.
用以确定物理特性(例如，血细胞比容)的另一技术可通过物理特性(例如，血细胞比容)的两个独立测量来实现。这可通过确定如下参数来获得：(a)流体样品在第一频率下的阻抗和(b)流体样品在显著高于第一频率的第二频率下的相位角。在该技术中，流体样品被建模成具有未知电抗和未知电阻的电路。利用该模型，可通过所施加的电压、在已知电阻器上的电压(例如，测试条固有电阻)、和在未知阻抗Vz上的电压来确定用于测量(a)的阻抗(由符号“│Z│”表示)；并且相似地，对于测量(b)而言，本领域中的技术人员可通过输入信号和输出信号之间的时间差来测量相位角。该技术的详细内容示于并描述于2011年9月2日提交的待审的临时专利申请序列号61/530,808(代理人案卷号DDI5215PSP)中，该专利以引用方式并入本文。还可利用用于确定流体样品的物理特性(例如，血细胞比容、粘度、温度、或密度)的其他合适的技术，诸如例如，美国专利4,919,770、美国专利7,972,861、美国专利申请公布2010/0206749、2009/0223834，或者由JoachimWegener、Charles R.Keese和IvarGiaever发表并且由Experimental Cell Research 259,158–166(2000)doi:10.1006/excr.2000.4919出版的可由http://www.idealibrary.coml在线获得的“Electric Cell–Substrate Impedance Sensing(ECIS)asaNoninvasiveMeanstoMonitortheKineticsofCell Spreading to ArtificialSurfaces”；由Takuya Kohma、Hidefumi Hasegawa、Daisuke Oyamatsu和SusumuKuwabata发表并且由Bull.Chem.Soc.Jpn.(第80卷，第1期，158–165(2007))出版的“UtilizationofACImpedanceMeasurements for Electrochemical Glucose SensingUsing Glucose Oxidase to Improve Detection Selectivity”，所有这些文献均以引用方式并入本文。Another technique to determine a physical property (eg, hematocrit) can be accomplished through two separate measurements of the physical property (eg, hematocrit). This can be obtained by determining the following parameters: (a) the impedance of the fluid sample at a first frequency and (b) the phase angle of the fluid sample at a second frequency significantly higher than the first frequency. In this technique, a fluid sample is modeled as a circuit with unknown reactance and unknown resistance. Using this model, the impedance (denoted by the symbol "│Z│"indicates); and similarly, for measurement (b), those skilled in the art can measure the phase angle by the time difference between the input signal and the output signal. Details of this technology are shown and described in co-pending Provisional Patent Application Serial No. 61/530,808 (Attorney Docket No. DDI5215PSP), filed September 2, 2011, which is incorporated herein by reference. Other suitable techniques for determining physical properties (e.g., hematocrit, viscosity, temperature, or density) of a fluid sample may also be utilized, such as, for example, U.S. Patent 4,919,770, U.S. Patent 7,972,861, U.S. Patent Application Publication 2010/0206749,2009/0223834 , or "Electric Cell–Substrate Impedance Sensing (ECIS) as a Noninvasive Means to Monitor the Kinetics of Cell Spreading to Artificial Surfaces”; published by Takuya Kohma, Hidefumi Hasegawa, Daisuke Oyamatsu, and Susumu Kuwabata and published by Bull. Chem. Soc. Jpn. (Vol. 80, No. 1, 158–165 (20 )) published "Utilization of ACImpedance Measurements for Electrochemical Glucose Sensing Using Glucose Oxidase to Improve Detection Selectivity", all of which are incorporated herein by reference.
可通过得知相位差(例如，相位角)和样品的阻抗幅值来获得用以确定物理特性(例如，血细胞比容、密度、或温度)的另一技术。在一个示例中，提供下述关系以用于估计样品的物理特性或阻抗特性(“IC”)：Another technique to determine a physical property (eg, hematocrit, density, or temperature) can be obtained by knowing the phase difference (eg, phase angle) and the impedance magnitude of the sample. In one example, the following relationship is provided for estimating the physical or impedance characteristics ("IC") of a sample:
IC＝M2*y1+M*y2+y3+P2*y4+P*y5 公式4.2IC＝M2 *y1 +M*y2 +y3 +P2 *y4 +P*y5 Formula 4.2
其中：M表示测量阻抗的量值│Z│(欧姆)；Among them: M represents the magnitude of the measured impedance│Z│(ohm);
P表示输入信号和输出信号之间的相位差(度)；P represents the phase difference (degrees) between the input signal and the output signal;
y1为约-3.2e-08±此处所提供数值的10％、5％或1％(取决于输入信号的频率，可为零)；y1 is about -3.2e-08 ± 10%, 5% or 1% of the value provided here (can be zero depending on the frequency of the input signal);
y2为约4.1e-03±此处所提供数值的10％、5％或1％(取决于输入信号的频率，可为零)；y2 is about4.1e -03 ± 10%, 5% or 1% of the value provided here (can be zero depending on the frequency of the input signal);
y3为约-2.5e+01±此处所提供数值的10％、5％或1％；y3 is about-2.5e +01 ± 10%, 5% or 1% of the values provided herein;
y4为约1.5e-01±此处所提供数值的10％、5％或1％(取决于输入信号的频率，可为零)；并且y4 is about 1.5e- 01 ± 10%, 5% or 1% of the value provided here (can be zero depending on the frequency of the input signal); and
y5为约5.0±此处提供的数值的10％、5％或1％(并且取决于输入信号的频率，可为零)。y5 is about 5.0 ± 10%, 5% or 1% of the values provided here (and may be zero depending on the frequency of the input signal).
此处应当指出的是，在输入AC信号的频率较高(例如，大于75kHz)的情况下，则与阻抗M的量值相关的参数项y1和y2可为本文给定的示例性值的±200％，使得这些参数项中的每一个可包括零或甚至为负值。在另一方面，在输入AC信号的频率较低(例如，小于75kHz)的情况下，与相位角P相关的参数项y4和y5可为本文给定的示例性值的±200％，使得这些参数项中的每个参数项可包括零或甚至为负值。此处应当指出的是，本文所用的H或HCT的量值通常等于IC的量值。在一个示例性的具体实施中，当H或HCT用于本专利申请中时，H或HCT等于IC。It should be noted here that in the case where the frequency of the input AC signal is high (for example, greaterthan 75kHz), then the parameter termsy1 and y2 related to the magnitude of the impedance M may be exemplary values given herein ±200% of , so that each of these parameter terms can include zero or even negative values. On the other hand, where the frequency of the input AC signal is low (e.g., less than 75 kHz), the parameter termsy4 andy5 related to the phase angle P may be ±200% of the exemplary values given herein, Such that each of these parameter terms may comprise zero or even a negative value. It should be noted here that the magnitude of H or HCT as used herein is generally equal to the magnitude of IC. In an exemplary implementation, when H or HCT is used in this patent application, H or HCT is equal to IC.
在另一个另选具体实施中，提供了公式4.3。公式4.3为二次方程关系的精确推导，且未使用公式4.2中的相位角。In another alternative implementation, Equation 4.3 is provided. Equation 4.3 is an exact derivation of the quadratic relationship and does not use the phase angle in Equation 4.2.
其中：in:
IC为阻抗特性[％]；IC is the impedance characteristic [%];
M为阻抗的量值[欧姆]；M is the magnitude of impedance [ohm];
y1为约1.2292e1±此处提供的数值的10％、5％或1％；y1 is about 1.2292e1 ± 10%, 5% or 1% of the values provided herein;
y2为约-4.3431e2±此处提供的数值的10％、5％或1％；y2 is about-4.3431e2 ± 10%, 5% or 1% of the values provided herein;
y3为约3.5260e4±此处提供的数值的10％、5％或1％。y3 is about3.5260e4 ± 10%, 5% or 1% of the values provided herein.
借助本文提供的多种部件、系统和见解，可参考图5理解用以检测在分析物测量期间由参考电极或反电极上的缺陷所引起的错误的技术。该技术涉及在步骤604处将流体样品(其可为生理样品或对照溶液样品)沉积在已插入到测量仪中(步骤602)的生物传感器(例如，如图3A-图3C所示的测试条的形式)上。一旦启动测量仪200，信号就将施加至测试条100(或其变体)，并且当样品沉积于测试腔室上时，所施加的信号将样品中的分析物(例如，葡萄糖)物理地转换到不同物理形式(例如，葡萄糖酸)中，这是因为分析物与测试腔室中试剂的酶促反应。当样品流入测试池的毛细通道中时，通过驱动至样品的另一个信号的输出获得样品的至少一个物理特性(步骤608)以及分析物浓度的估计值(步骤610)。基于所获得的物理特性(步骤608)和估计的分析物浓度(步骤610)，限定取样时隙(步骤612)，在该取样时隙处测量在测试序列期间来自样品的信号输出(步骤614)并且将此信号在主程序中用于计算分析物浓度。具体地，获得物理特性的步骤(步骤608)可包括将第一信号施加至样品以测量样品的物理特性，而引发酶促反应的步骤606可涉及将第二信号驱动至样品，并且测量步骤(步骤614)可需要评估所述至少两个电极在测试序列启动之后的时间点处的输出信号，其中该时间点被设定成(在步骤612处)是至少所测量的或估计的物理特性(步骤608)和所估计的分析物浓度(步骤610)的函数。With the various components, systems, and insights provided herein, techniques to detect errors during analyte measurements caused by defects on the reference or counter electrode can be understood with reference to FIG. 5 . The technique involves depositing a fluid sample (which may be a physiological sample or a control solution sample) at step 604 on a biosensor (e.g., a test strip as shown in FIGS. 3A-3C ) that has been inserted into the meter (step 602). form). Once the meter 200 is activated, a signal is applied to the test strip 100 (or a variant thereof), and when the sample is deposited on the test chamber, the applied signal physically converts the analyte (e.g., glucose) in the sample to a different physical form (eg, gluconic acid) due to the enzymatic reaction of the analyte with the reagents in the test chamber. As the sample flows into the capillary channel of the test cell, at least one physical characteristic of the sample (step 608) and an estimate of the analyte concentration (step 610) are obtained by the output of another signal driven to the sample. Based on the obtained physical properties (step 608) and estimated analyte concentrations (step 610), sampling time slots are defined (step 612) at which to measure the signal output from the sample during the test sequence (step 614) And this signal is used in the main program to calculate the analyte concentration. Specifically, the step of obtaining a physical property (step 608) may include applying a first signal to the sample to measure the physical property of the sample, while the step 606 of initiating an enzymatic reaction may involve driving a second signal to the sample, and the step of measuring ( Step 614) may entail evaluating the output signals of the at least two electrodes at a point in time after initiation of the test sequence, where the point in time is set (at step 612) to be at least the measured or estimated physical property ( Step 608) and the estimated analyte concentration (step 610).
(在步骤612中)确定测试序列TS期间的适当时间点(或时间间隔)作为所测量的或估计的物理特性的函数，该时间点(或时间间隔)可通过使用被编程到系统的微处理器中的查找表来确定。例如，可提供查找表，所述查找表允许系统利用样品的测量或已知物理特性(例如，血细胞比容或粘度)来选择用于分析物(例如，葡萄糖或酮)的适当取样时间。Determine (in step 612) the appropriate point in time (or time interval) during the test sequence TS as a function of the measured or estimated physical characteristic, which time point (or time interval) can be programmed into the system by using the micro lookup table in the processor to determine. For example, a look-up table may be provided that allows the system to use measurements of the sample or known physical properties (eg, hematocrit or viscosity) to select an appropriate sampling time for an analyte (eg, glucose or ketones).
具体地，可基于分析物的先前估计和所测量的或已知物理特性来确定适当取样时间点，以获得相比于参考值给出最小误差或偏差的适当取样时间。在该技术中，提供了查找表，在所述查找表中，限定的取样时间点与(a)估计的分析物浓度和(b)样品的物理特性相关。例如，可将表1编程到测量仪中以提供矩阵，在该矩阵中，所估计分析物的定性类别(低、中等和高葡萄糖)形成主列，并且所测量的或估计的物理特性的定性类别(低、中等、和高)形成标题行。在第二列中，t/Hct为相对42％标称血细胞比容而言的每％血细胞比容差的经实验确定的时间偏移值。例如，“中等葡萄糖”下的55％血细胞比容将指示出(42-55)*90＝-1170ms的时间偏移。将-1170毫秒的时间加到约5000毫秒的初始测试时间，从而给出(5000-1170＝3830毫秒)～3.9秒。In particular, an appropriate sampling time point may be determined based on previous estimates of the analyte and measured or known physical properties to obtain an appropriate sampling time that gives minimal error or deviation compared to a reference value. In this technique, a look-up table is provided in which defined sampling time points are related to (a) estimated analyte concentrations and (b) physical properties of the sample. For example, Table 1 can be programmed into the meter to provide a matrix in which the qualitative classes of estimated analytes (low, medium and high glucose) form the main columns and the qualitative classes of the measured or estimated physical properties The categories (low, medium, and high) form the header row. In the second column, t/Hct is the experimentally determined time offset value per % hematocrit error relative to 42% nominal hematocrit. For example, a 55% hematocrit at "medium glucose" would indicate a time shift of (42-55)*90=-1170 ms. Adding the time of -1170 milliseconds to the initial test time of about 5000 milliseconds gives (5000-1170 = 3830 milliseconds) -3.9 seconds.
表1Table 1
该系统应对生物传感器的输出信号进行取样或测量的时间Tss(即，指定取样时间)是基于所估计的分析物的定性类别和所测量的或估计的物理特性两者的，并且是基于实际生理流体样品的大样品量的回归分析来预定的。申请人指出，适当的取样时间是从测试序列启动测量的，但可使用任何适当的数据以便确定何时对输出信号进行取样。实际上，该系统可被编程以在整个测试序列期间的适当取样时间间隔处对输出信号进行取样，诸如例如，每隔100毫秒或甚至短至约每隔1毫秒进行一次取样。通过在测试序列期间对整个信号输出瞬态进行取样，该系统可在测试序列接近结束时进行全部所需的计算，而非尝试使取样时间与设置时间点同步，这样可由于系统延迟而引入计时误差。The time Tss (i.e., the specified sampling time) at which the system should sample or measure the output signal of the biosensor is based on both the estimated qualitative class of the analyte and the measured or estimated physical property, and is based on the actual Regression analysis of large sample volumes of physiological fluid samples is intended. Applicants indicate that a suitable sampling time is measured from the start of the test sequence, but any suitable data may be used in order to determine when to sample the output signal. Indeed, the system can be programmed to sample the output signal at appropriate sampling intervals throughout the test sequence, such as, for example, every 100 milliseconds or even as short as about every 1 millisecond. By sampling the entire signal output transient during the test sequence, the system can perform all required calculations near the end of the test sequence, rather than attempting to synchronize the sampling time with a set point in time, which can introduce timing due to system delays error.
申请人在下文中将相对于生理流体样品中葡萄糖的特定分析物来讨论查找表1。血糖的定性类别限定在表1的第一列中，其中低于约70mg/dL的低血糖浓度被指定为“低葡萄糖”；高于约70mg/dL但低于约250mg/dL的血糖浓度被指定为“中等葡萄糖”；并且高于约250mg/dL的血糖浓度被指定为“高葡萄糖”。Applicants will hereinafter discuss Lookup Table 1 with respect to a specific analyte of glucose in a physiological fluid sample. Qualitative categories of blood glucose are defined in the first column of Table 1, wherein low blood glucose concentrations below about 70 mg/dL are designated "low glucose"; blood glucose concentrations above about 70 mg/dL but below about 250 mg/dL are designated as "low glucose" are designated as "moderate glucose"; and blood glucose concentrations above about 250 mg/dL are designated as "high glucose."
在测试序列期间，可通过对适当时间点处，通常在典型的10秒测试序列期间的5秒处的信号进行取样来获得“所估计的分析物”。在该5秒时间点(在下文中，“Tes”)处被取样的测量允许获得对分析物(在这种情况下，血糖)的精确估计。该系统可随后参考查找表(例如，表1)来确定在指定取样时间Tss处何时从测试腔室测量信号输出，该确定基于两个标准：(a)在Tes处所估计的分析物和(b)样品的物理特性的定性值。对于标准(b)而言，物理特性的定性值被分解成三个子类别：低Hct、中等Hct、和高Hct。因此，如果所测量的或估计的物理特性(例如，血细胞比容)较高(例如，高于46％)并且所估计的葡萄糖也较高，则根据表1，该系统用来测量测试腔室的信号输出的测试时间Tss将为约3.6秒。另一方面，如果所测量的血细胞比容较低(例如，低于38％)并且所估计的葡萄糖较低，则根据表1，该系统用来测量测试腔室的信号输出的指定取样测试时间Tss将为约5.5秒。During the test sequence, an "estimated analyte" can be obtained by sampling the signal at appropriate time points, typically at 5 seconds during a typical 10 second test sequence. The measurements sampled at this 5 second time point (hereinafter "Tes") allow to obtain an accurate estimate of the analyte (in this case, blood glucose). The system can then refer to a lookup table (e.g., Table 1) to determine when to measure signal output from the test chamber at a specified sampling time Tss, based on two criteria: (a) the estimated analyte at Tes and ( b) Qualitative values of the physical properties of the samples. For criterion (b), qualitative values of physical properties are broken down into three subcategories: low Hct, medium Hct, and high Hct. Thus, if the measured or estimated physical characteristic (e.g., hematocrit) is high (e.g., above 46%) and the estimated glucose is also high, then according to Table 1, the system used to measure the test chamber The test time Tss of the signal output will be about 3.6 seconds. On the other hand, if the measured hematocrit is low (e.g., below 38%) and the estimated glucose is low, the specified sampling test time for the system to measure the signal output of the test chamber according to Table 1 Tss will be about 5.5 seconds.
一旦在指定时间(其由所测量的或估计的物理特性控制)处测量测试腔室的信号输出IT，随后就将信号IT用于下文的公式5中以计算分析物浓度(在这种情况下，葡萄糖)。Once the signal outputIT of the test chamber is measured at a specified time (which is governed by a measured or estimated physical property), the signalIT is then used in Equation 5 below to calculate the analyte concentration (at this case, glucose).
其中in
G0表示分析物浓度；G represents the concentration of the analyte;
IT表示从在指定取样时间Tss处测量的结束信号之和确定的信号(与分析物浓度成比例)，该信号可为在指定取样时间Tss处测量的总电流；IT represents the signal (proportional to the analyte concentration) determined from the sum of the end signals measured at the specified sampling time Tss, which signal may be the total current measured at the specified sampling time Tss;
斜率表示从该特定测试条所在的一批测试条的校准测试中获得的值并且通常为约0.02；并且The slope represents the value obtained from a calibration test of the batch of test strips in which that particular test strip is located and is typically about 0.02; and
截距表示从该特定测试条所在的一批测试条的校准测试中获得的值并且通常为约0.6至约0.7。The intercept represents the value obtained from a calibration test of the batch of test strips in which that particular test strip was included and is typically about 0.6 to about 0.7.
应当指出的是，施加第一信号和驱动第二信号的步骤是按顺序的，其中顺序可为首先施加第一信号随后驱动第二信号，或者两个信号按顺序地重叠；另选地，首先驱动第二信号然后施加第一信号，或者两个信号按顺序地重叠。另选地，施加第一信号和驱动第二信号可同时发生。It should be noted that the steps of applying the first signal and driving the second signal are sequential, wherein the order can be first applying the first signal and then driving the second signal, or the two signals are sequentially overlapped; alternatively, first The second signal is driven and then the first signal is applied, or the two signals overlap sequentially. Alternatively, applying the first signal and driving the second signal may occur simultaneously.
在该方法中，施加第一信号的步骤涉及将由适当功率源(例如，测量仪200)提供的交变信号引导至样品，使得从交变信号的输出确定样品的物理特性。被检测的物理特性可为粘度、血细胞比容或密度中的一者或多者。所述引导步骤可包括驱动不同相应频率下的第一交变信号和第二交变信号，其中第一频率低于第二频率。优选的是，第一频率比第二频率低至少一个数量级。例如，第一频率可为约10kHz至约100kHz范围内的任何频率，第二频率可为约250kHz至约1MHz或更高。如本文所用，短语“交变信号”或“振荡信号”可具有极性交变的信号的一些部分、或全检查电压电信号、或具有直流电偏移的交流电流、或甚至与直流电流信号结合的多向信号。In the method, the step of applying a first signal involves directing an alternating signal provided by a suitable power source (eg, gauge 200 ) to the sample such that a physical property of the sample is determined from the output of the alternating signal. The physical property detected may be one or more of viscosity, hematocrit or density. The step of directing may include driving the first alternating signal and the second alternating signal at different respective frequencies, wherein the first frequency is lower than the second frequency. Preferably, the first frequency is at least an order of magnitude lower than the second frequency. For example, the first frequency can be any frequency in the range of about 10 kHz to about 100 kHz, and the second frequency can be about 250 kHz to about 1 MHz or higher. As used herein, the phrase "alternating signal" or "oscillating signal" may have portions of the signal that alternate in polarity, or a full check voltage electrical signal, or an alternating current with a direct current offset, or even combined with a direct current signal multidirectional signal.
基于所述技术的附加研究对表1的进一步精化允许申请人设计出下文所示的表2。Further refinement of Table 1 based on additional studies of the described techniques allowed applicants to design Table 2 shown below.
表2.相对于所估计的G和所测量的或估计的物理特性的指定取样时间TssTable 2. Specified sampling times Tss with respect to estimated G and measured or estimated physical properties
如在表1中，将所测量的或估计的物理特性与所估计的分析物浓度一起用于表2中以导出待测量的样品的时间TSS。例如，如果所测量的特性为约30％并且所估计的葡萄糖(例如，通过在约2.5至3秒的Tes处进行取样)为约350，则微控制器应对流体进行取样的时间为约7秒。在另一示例中，在所估计的葡萄糖(在Tes处测量的)为约300mg/dL并且所测量的或估计的物理特性为60％的情况下，指定取样时间TSS将为约3.1秒。As in Table 1, the measured or estimated physical properties are used in Table 2 together with the estimated analyte concentration to derive the time TSS of the sample to be measured. For example, if the measured characteristic is about 30% and the estimated glucose (e.g., by sampling at Tes at about 2.5 to 3 seconds) is about 350, the time the microcontroller should sample the fluid is about 7 seconds . In another example, where the estimated glucose (measured at Tes) is about 300 mg/dL and the measured or estimated physical characteristic is 60%, the specified sampling time TSS would be about 3.1 seconds.
对于结合表2使用的实施方案而言，所估计的葡萄糖浓度由下述公式提供：For the embodiments used in conjunction with Table 2, the estimated glucose concentration is provided by the following formula:
其中Gest表示所估计的葡萄糖浓度；where Gest represents the estimated glucose concentration;
IE为在约2.5秒处测量的信号；IE is the signal measured at about 2.5 seconds;
x1为斜率(例如，x1＝1.3e01)；x1 is the slope (eg, x1 =1.3e01);
x2为截距(例如，x2＝6.9e02)x2 is the intercept (eg, x2 =6.9e02)
由所估计的葡萄糖，可利用下述公式来确定葡萄糖浓度：From the estimated glucose, the glucose concentration can be determined using the following formula:
其中：GO表示葡萄糖浓度；Wherein:GO represents glucose concentration;
IS为在得自表2的指定取样时间Tss处测量的信号；IS is the signal measured at the specified sampling time Tss from Table 2;
x3为斜率(例如，x3＝9.6)；并且x3 is the slope (eg, x3 =9.6); and
x4为截距(例如，x4＝4.8e02)。x4 is the intercept (eg, x4 =4.8e02).
尽管申请人的技术可仅指定一个取样时间点，但该方法可包括对所需的多个时间点进行取样，诸如例如，从测试序列启动时连续地(例如，在指定取样时间处，诸如每隔1毫秒至每隔100毫秒)对信号输出进行取样，直到启动之后至少约10秒，并且在接近测试序列结束时存储取样结果以便进行处理。在该变型中，在指定取样时间处(其可不同于预定取样时间点)的取样信号输出为用于计算分析物浓度的值。Although applicant's technique may specify only one sampling time point, the method may include sampling as many time points as desired, such as, for example, continuously from the start of the test sequence (e.g., at a specified sampling time, such as every The signal output is sampled every 1 millisecond to every 100 milliseconds) until at least about 10 seconds after start-up, and the sampled results are stored for processing near the end of the test sequence. In this variation, the sampled signal at a specified sampling time (which may be different from the predetermined sampling time point) is output as the value used to calculate the analyte concentration.
应当指出的是，在优选的实施方案中，在血细胞比容的估计之前执行用于该值(其与分析物(例如，葡萄糖)浓度在一定程度上成比例)的信号输出的测量。另选地，可在初始葡萄糖浓度的测量之前估计血细胞比容水平。在任一种情况下，通过公式3.3并利用在2.5秒或5秒中的约一者处进行取样的IE(如在图7中所示)来获得所估计的葡萄糖测量GE，通过公式4获得物理特性(例如，Hct)，通过利用信号瞬态1000在指定取样时间点处所测量的信号输出ID(例如，在3.5秒或6.5秒处进行取样的所测量信号输出ID)获得葡萄糖测量G。It should be noted that in a preferred embodiment the measurement of the signal output for this value (which is to some extent proportional to the analyte (eg glucose) concentration) is performed prior to the estimation of the hematocrit. Alternatively, the hematocrit level may be estimated prior to the measurement of the initial glucose concentration. In either case, the estimated glucose measure GE is obtained by Equation 3.3 and using IE sampled at about one of 2.5 seconds or 5 seconds (as shown in FIG. 7 ), by Equation 4A physical characteristic (e.g.,Hct ) is obtained by utilizing the signal transient 1000 to obtain a measured signal output ID at a specified sampling time point (e.g., a measured signal output ID sampled at 3.5 seconds or 6.5 seconds) to obtain a glucose measurement g.
在以下专利中示出和描述了其它用于确定分析物浓度或值的技术：PCT/GB2012/053276(代理人案卷号DDI 5220WOPCT，2012年12月28日提交)、PCT/GB2012/053279(代理人案卷号DDI5246WOPCT，2012年12月28日提交)、PCT/GB2012/053277(代理人案卷号DDI5228WOPCT，2012年12月28日提交)，所有专利申请在此以引用方式并入，如同本文以附属于本专利申请的附录的副本完整示出一样。Other techniques for determining analyte concentrations or values are shown and described in: PCT/GB2012/053276 (Attorney Docket No. DDI 5220WOPCT, filed December 28, 2012), PCT/GB2012/053279 (Attorney Attorney's Docket No. DDI5246WOPCT, filed December 28, 2012), PCT/GB2012/053277 (Attorney's Docket No. DDI5228WOPCT, filed December 28, 2012), all patent applications are hereby incorporated by reference as if attached herein The same is shown in full in the copy of the appendix of this patent application.
已由申请人确定的是，工作电极中的一个工作电极上的导电表面的任何问题(例如，结垢)将减少连接至该电极的输出信号瞬态。这将表现为具有低偏置的低电流瞬态。通常，这些异常结果由我们的系统错误检查来检测(该系统错误检查示于并描述于2013年6月27日提交的名称为：FILL ERROR TRAP FOR AN ANALYTE MEASUREMENT DETERMINED FROM ASPECIFIED SAMPLING TIME DERIVED FROM A SENSED PHYSICAL CHARACTERISTIC OF THESAMPLE CONTAINING THE ANALYTE的美国专利申请SN 13929404(代理人案卷号DDI5268USNP)中，该专利申请以引用方式并入本申请)。该系统错误检查寻找第一工作电极信号瞬态和第二工作电极信号瞬态之间的较大差值。It has been determined by the applicant that any problem (eg, fouling) of the conductive surface on one of the working electrodes will reduce output signal transients connected to that electrode. This will appear as a low current transient with low bias. Typically, these abnormal results are detected by our system error checking (shown and described in the June 27, 2013 submission titled: FILL ERROR TRAP FOR AN ANALYTE MEASUREMENT DETERMINED FROM ASPECIFIED SAMPLING TIME DERIVED FROM A SENSED US Patent Application SN 13929404 (Attorney Docket No. DDI5268USNP) for PHYSICAL CHARACTERISTIC OF THESAMPLE CONTAINING THE ANALYTE, which is incorporated herein by reference). The system error checking looks for large differences between the first working electrode signal transient and the second working electrode signal transient.
我们已确定如果在反电极或参考电极上发生结垢，则系统在将由反电极或参考电极10的降低效率限制时将在第一工作电极12和第二工作电极14两者上产生低信号输出瞬态。当第一工作电极12和第二工作电极14两者将受到类似的影响时，我们先前的系统错误检查此处将不运行。因此需要将限制该潜在故障模式的系统错误陷阱。We have determined that if fouling occurs on the counter or reference electrode, the system will produce a low signal output on both the first working electrode 12 and the second working electrode 14 when it will be limited by the reduced efficiency of the counter or reference electrode 10 transient. As both the first working electrode 12 and the second working electrode 14 would be similarly affected, our previous system error checking would not run here. System error traps that will limit this potential failure mode are therefore needed.
因此，我们已设计出这种确定何时通告由于测试条的结垢或受损的参考电极而产生错误的问题的解决方案。具体地，申请人已设计出测试，其中从靠近指定取样时间TSS测量的第一电极的输出信号瞬态相对于靠近预定取样时间TPdt测量的第一工作电极的输出信号瞬态的量值确定第一差值。另外，在该测试中，从靠近指定取样时间TSS测量的第二电极的输出信号瞬态相对于靠近预定取样时间TPdt测量的第二工作电极的输出信号瞬态的量值确定第二差值。如果第一差值或第二差值中的任一个小于偏置阈值β，则错误被标记或存储在系统中。Therefore, we have devised a solution to the problem of determining when to signal an error due to fouling of the test strip or a damaged reference electrode. Specifically, Applicants have devised a test in which the magnitude of the output signal transient from a first electrode measured near a specified sampling time TSS relative to the output signal transient of a first working electrode measured near a predetermined sampling time TPdt A first difference is determined. Additionally, in this test, a second difference is determined from the magnitude of the output signal transient of the second electrode measured near the specified sampling time TSS relative to the output signal transient of the second working electrode measured near the predetermined sampling time TPdt value. If either the first difference or the second difference is less than the offset threshold β, an error is flagged or stored in the system.
将要触发错误的评估方法的数学表达式通过公式8.1和8.2示出：The mathematical expression of the evaluation method that will trigger the error is shown by Equations 8.1 and 8.2:
其中in
(第一工作电极12的)输出信号Iwe1(微安)和(第二工作电极14的)输出信号Iwe2(微安)中的每个输出信号在如前面所讨论的“指定取样时间”(或TSS)和预定取样时间TPdt处测量，并且β为约10纳安至1000纳安的任何值，并且优选地为约100纳安。Each of the output signal Iwe1 (microamperes) (of the first working electrode 12) and the output signal Iwe2 (microamperes) (of the second working electrode 14 ) at a "specified sampling time" as previously discussed (or TSS ) and a predetermined sampling time TPdt , and β is anywhere from about 10 nanoamperes to 1000 nanoamperes, and preferably about 100 nanoamperes.
参见图5，示出了在测试分析物(例如，血液或对照溶液)的分析物测试测量或测定期间的我们的错误检查过程的新型具体实施。在步骤604处，一滴测试分析物沉积于生物传感器上(即，图3A-图3C)，其中该插入的生物传感器先前插入(步骤602)到测量仪中(图1A或图1B)。在步骤604处，测量仪循环通过填充检测序列(图4A)并且一旦测量仪(经由图2A或图2B中的其微控制器300)检测到流体，测量仪就移动到步骤606，在步骤606处将测试序列计时器Ts设定为零(图4A)。Referring to Figure 5, a novel implementation of our error checking process during an analyte test measurement or determination of a test analyte (eg, blood or control solution) is shown. At step 604, a drop of test analyte is deposited on the biosensor (ie, FIG. 3A-3C) where the inserted biosensor was previously inserted (step 602) into the meter (FIG. 1A or FIG. 1B). At step 604, the gauge cycles through the fill detection sequence (FIG. 4A) and once the gauge detects fluid (via its microcontroller 300 in FIG. 2A or FIG. 2B), the gauge moves to step 606, where Set the test sequence timer Ts to zero (FIG. 4A).
测量仪通过将时变信号(例如，交变信号或振荡信号)驱动到分析物样品中并且测量来自样品(经由图3A中的感测电极19a和20a)的反应输出开始测量分析物的物理特性。测量仪还可将直接信号(即，直流(D.C.)信号)驱动到分析物样品中并且在预定时间处(在测试序列期间)进行测量以获得所估计的分析物值。测量仪还在步骤612处基于所测量的物理特性(例如，在步骤608处的阻抗Z)和所估计的分析物浓度(得自步骤610)、使用本文所述的查找表或在PCT/GB2012/053276(代理人案卷号DDI5220WOPCT)；PCT/GB2012/053279(代理人案卷号DDI5246WOPCT)；或PCT/GB2012/053277(代理人案卷号DDI5228WOPCT)中所述的算法来确定指定取样时间(“TSS”)。The meter begins measuring a physical property of the analyte by driving a time-varying signal (e.g., an alternating or oscillating signal) into the analyte sample and measuring the response output from the sample (via sensing electrodes 19a and 20a in FIG. 3A ). . The meter can also drive a direct signal (ie, a direct current (DC) signal) into the analyte sample and take measurements at predetermined times (during the test sequence) to obtain estimated analyte values. The meter is also at step 612 based on the measured physical property (e.g., impedance Z at step 608) and the estimated analyte concentration (from step 610), using a look-up table as described herein or in PCT/GB2012 /053276 (attorney docket number DDI5220WOPCT); PCT/GB2012/053279 (attorney docket number DDI5246WOPCT); or PCT/GB2012/053277 (attorney docket number DDI5228WOPCT) to determine the specified sampling time (“TSS ").
一旦测量仪已从步骤612获得指定取样时间TSS，测量仪就将在步骤614处在测试期间的指定时间TSS处取样或测量来自分析物样品(经由工作电极1和2)的输出信号。测量仪还将在步骤616处在预定时隙处取样或测量来自分析物样品(经由工作电极1和2)的输出信号。在该实施方案中，我们已将该预定时隙选择为与用于在测试序列中的大约2.5秒(例如，TPdt＝Tes)处估计分析物测量的时隙相同。Once the meter has obtained the specified sampling time TSS from step 612 , the meter will sample or measure the output signal from the analyte sample (via working electrodes 1 and 2 ) at the specified time TSS during the test at step 614 . The meter will also sample or measure the output signal from the analyte sample (via working electrodes 1 and 2 ) at step 616 at predetermined time slots. In this embodiment, we have chosen this predetermined time slot to be the same as the time slot used to estimate the analyte measurement at approximately 2.5 seconds (eg, TPdt = Tes) in the test sequence.
在步骤618处，测量仪将计算第一工作电极12在这两个时隙(即，指定时间TSS和预定时间TPdt)处的响应中的第一差动Δ1。在步骤620处，测量仪将计算第二工作电极14在这两个时隙(即，指定时间TSS和预定时间TPdt)处的响应中的第二差动Δ2。At step 618, the meter will calculate the first differential Δ1 in the response of the first working electrode 12 at these two time slots (ie, the specified time TSS and the predetermined time TPdt ). At step 620, the meter will calculate the second differential Δ2 in the response of the second working electrode 14 at these two time slots (ie, the specified time TSS and the predetermined time TPdt ).
测量仪可直接从步骤620进入到步骤628，由此，可抵靠阈值β检查差动Δ1或Δ2中的每个差动。阈值β可被指定为所测量的物理特性(例如，血细胞比容)的函数。应当指出的是，偏置阈值β可以是约30纳安至1000纳安的任何值。基于我们最初的实验，我们已为该阈值选择100纳安。如果差动Δ1或Δ2中的任一个小于偏置阈值β，则可在步骤630处设定错误标记用于在经由主程序进行的测试序列结束时进行显示(或者测试测量序列可随着错误的显示而立即终止)。应当指出的是，其中Δ1或Δ2是负值，该系统可获得绝对值用于与预定阈值进行比较。From step 620 the gauge may proceed directly to step 628 whereby each of the differentials Δ1 or Δ2 may be checked against a threshold value β. The threshold β can be specified as a function of the measured physical property (eg, hematocrit). It should be noted that the bias threshold β can be anywhere from about 30 nanoamperes to 1000 nanoamperes. Based on our initial experiments, we have chosen 100 nanoamps for this threshold. If either of the differentials Δ1 or Δ2 is less than the offset threshold β, an error flag may be set at step 630 for display at the end of the test sequence via the main program (or the test measurement sequence may follow the erroneous displayed and terminated immediately). It should be noted that where Δ1 or Δ2 is a negative value, the system can obtain an absolute value for comparison with a predetermined threshold.
针对测试条的某些实施方案，考虑到该错误的输出信号瞬态与低温下的输出信号瞬态的相似性，我们可将该错误检查在低于一定温度阈值(例如T阈值～16℃)下设计成禁用，以避免在低温下进行的大量的良好测量被消除。我们还已经配置了该测试，使得该测试可限于其中已估计的分析物小于给定的阈值(例如，葡萄糖浓度Gmax小于275mg/dL)的实例。为了更好地控制假阳性，我们还可设定另一个先决条件，其中只要所测量的物理特性(例如，血细胞比容或Z)小于最大值(例如，Zmax)就执行该测试。For some embodiments of the test strip, we may check for this error below a certain temperaturethreshold (e.g., Tthreshold ~ 16° C.), given the similarity of the output signal transient of this error to that at low temperatures. The lower is designed to be disabled to avoid the large number of good measurements taken at low temperatures being eliminated. We have also configured the test so that it can be limited to instances where the estimated analyte is less than a given threshold (eg, glucose concentration Gmax less than 275 mg/dL). To better control false positives, we can also set another precondition, where the test is performed as long as the measured physical property (eg, hematocrit or Z) is less than a maximum value (eg, Zmax).
根椐测试条和测量仪的参数，这些阈值条件可被建立为图5所示的方法中的先决条件步骤622、624和626。尽管已为我们的测试条和测量系统的特定配置建立了这些先决条件，但是应当理解，这些条件不需要作为该参考电极错误检查的一部分。Depending on the parameters of the test strip and meter, these threshold conditions may be established as prerequisite steps 622, 624 and 626 in the method shown in FIG. Although these prerequisites have been established for our particular configuration of test strips and measurement systems, it should be understood that these conditions need not be part of this reference electrode error check.
虽然已经根据特定的变型和示例性附图描述了本发明，但是本领域的普通技术人员将认识到本发明不限于所描述的变型或附图。此外，其中上述方法和步骤指示按特定次序发生的特定事件，本文旨在某些特定步骤不必一定按所描述的次序执行，而是可以按任意次序执行，只要该步骤允许实施方案能够实现其预期目的。因此，如果存在本发明的变型并且所述变型属于可在权利要求书中找到的本发明公开内容或等效内容的实质范围内，则本专利旨在也涵盖这些变型。While the invention has been described in terms of particular variations and exemplary figures, those of ordinary skill in the art will recognize that the invention is not limited to the described variations or figures. Furthermore, where the methods and steps described above indicate specific events occurring in a specific order, it is intended herein that certain specific steps need not necessarily be performed in the order described, but may be performed in any order so long as the steps allow the embodiment to achieve its intended Purpose. Therefore, if there are variations of the invention and said variations fall within the essential scope of the disclosure of the invention or equivalents found in the claims, the patent intends to cover these variations as well.
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| US14/605,501US9423374B2 (en) | 2015-01-26 | 2015-01-26 | Reference electrode error trap determined from a specified sampling time and a pre-determined sampling time |
| US14/605501 | 2015-01-26 | ||
| PCT/EP2016/051455WO2016120212A1 (en) | 2015-01-26 | 2016-01-25 | Reference electrode error trap determined from a specified sampling time and a pre-determined sampling time |
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| CN201680007333.4APendingCN107209141A (en) | 2015-01-26 | 2016-01-25 | The reference electrode error trap determined from predetermined sampling time interval and scheduled sampling time |
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| EP (1) | EP3250916B1 (en) |
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